Respiratory viral infections are the most frequently occurring diseases worldwide, clinically recognized as “common cold,” flu, bronchiolitis, pneumonia, and so on, with approximately 200 million viral pneumonia cases alone annually. Adaptive and innate immune systems, together with airway epithelial tissues, become a major battlefield against viral infections, and a robust immune response is essential for viral clearance. However, an immunological paradox in various respiratory viral infections is that strong immune and inflammatory responses usually lead to tissue inflammation, cytokine storm, acute lung dysfunction, chronic tissue damage, or the exacerbation of pre-existing inflammatory diseases. Reversely, persistent or chronic lung inflammation can interfere with protective immune responses in combating new infections. Complex interactions between infections and inflammations were more specifically derived from the overlapped cellular and molecular compositions that are protective in anti-viral immune defenses but can be pathogenic to induce tissue damage. In innate immune responses, monocytes, macrophages (MΦs), granulocytes, and airway epithelial cells mediate viral entry into host cells and produce various inflammatory mediators partially for viral clearance and often lead to tissue damage. In adaptive immune responses, T cells respond to the viral peptides presented by viral-infected antigen-presenting cells (APCs) to control viral infections. However, T cells can induce both protective and pathogenic responses, as Yin-Yang interactions at the cellular and molecular levels or as a mysterious Roman mythological figure “Janus” with two faces looking in opposite directions.
Chronic obstructive pulmonary disease (COPD) designates a complex of lung inflammatory pathologies, including emphysema, chronic bronchitis, chronic bronchiolitis,[2,3] which manifest persistent or progressive airflow limitation, lung dysfunction, and airway tissue damage and remodeling. Ranked as the third leading cause of global mortality following heart diseases and stroke, COPD killed >3 million people worldwide in 2016 and affected around 10% and 25% of middle-aged and senior (>70 years of age) populations, respectively, in the Australian cohorts. In etiology, COPD involves mixed genetics and environmental factors, including genetic elements prone to inflammatory pathology, exacerbation by bacterial and viral infections, and exposure to various environmental pollutants.[6,7] In pathogenesis, COPD is initiated by inflammatory responses through a complex interaction of airway epithelial, stromal, and immune cells, together with systemic inflammatory cells and mediators. These interactions further lead to functional dysregulation, structural damage, and obstructive reconstruction of airway tissues, reducing respiratory capacity symptomatically. Since various innate immune mechanisms in respiratory viral infections and COPD have been comprehensively reviewed,[9–11] we briefly summarize key innate compositions below and emphasize T cell-mediated immune responses as critical viral-specific responders and regulators in the crosstalk between lung infections and inflammations.
Comorbidity and Innate Immune Responses in Respiratory Viral Infections and COPD
Considerably abundant evidence supports that viral infections are critical factors to induce the pathogenesis and acute exacerbation of COPD (AECOPD) [Table 1]. Implementation of molecular genetic approaches has facilitated the demonstration of viral infections in half of all AECOPD,[12,13] with the positivity of viral genetic elements ranging approximately from 22% to 64% in AECOPD patients from 20 cohorts[14,15] and 24 cohorts, or at an average of 36.7% in COPD patients from 28 cohorts. The positive rate of each respiratory virus in AECOPD varies, with human rhinovirus (HRV) at a range of 12% to 63% as the most detected virus [Table 1]. Stable COPD patients show a lower percentage of a total viral infection rate in comparison to AECOPD patients. For example, 12% or 19% of total viral infection has been detected in stable COPD. The most common viruses detected in stable COPD were respiratory syncytial virus (RSV) (24%), HRV (7.3%), and coronavirus (5.9%) in the London cohort. Comorbidity rates between respiratory viral infections and COPD are impacted by various confounding factors. For example, a low viral prevalence in the London cohort was likely confounded by a relatively high influenza vaccination rate (74%).
Table 1 -
Viral pathogeneses, innate immune responses, and comorbidity in COPDs.
||Features and pathogeneses
||Comorbidity in COPD
|Human rhinovirus (HRV)
||Positive sense, single-stranded RNA, picornaviridae family.More than 150 serotypes.More than 60% serotypes bind ICAM-1 to invade bronchial epithelial cells and alveolar MΦs.
||Replicates in bronchial epithelial cells to produce CXCL10, IL-8.Infects alveolar MΦs to produce TNF-α, CXCL10, CCL5 (RANTES), eotaxin-1, ICAM-1, and neutrophil elastase via NF-κB activation.Production of CXCL10, CCL5, and TNF-α attracts naïve T cells.Infects primary human airway fibroblast to produce chemokines for neutrophils.
||HRV causes most frequent viral infections in COPD.HRV is positive in 17.3%, 16.4% of 2000 COPD cases.HRV is positive in 12% to 63% childhood community-acquired pneumonia and/or bronchiolitis from 19 cohorts.90% HRV infections in COPD patients cause exacerbation in three cohorts.
|Respiratory syncytial virus (RSV)
||Negative single-stranded RNA-enveloped virus.A common cause for bronchiolitis.Enter host cells through micropinocytosis followed by proteolysis of the fusion (F) protein.
||Induces high expression of inflammatory markers.Interacts with PRR (TLR3) in lung epithelial cells to produce cytokine and inflammatory mediators via NF-κB activation and further recruit neutrophils and activate T cells.RSV RNA interaction with TLR3 is associated with declining lung function in COPD.
||RSV is positive in 5.3% exacerbated COPD.RSV is 9.9% positive in 2000 COPD cases.
||Segmented negative-sense, mostly single-stranded, orthomyxoviridae.Causes seasonal flu.HA and NA interact with N-linked glycans to induce endocytosis for cell entry.
||Replicates in alveolar epithelial cells to recruit CCR2hi inflammatory monocytes and induce alveolar MΦ apoptosis.Infects neutrophils to induce apoptosis, impair phagocytosis, and reduce reactive oxygen species production, further causing tissue damage and inflammatory pathology.[31,32]Infects alveolar MΦs to produce TNF-α.
||Influenza virus is positive in 7.4% exacerbated COPD.Influenza virus is 7.8% positive in 2000 COPD cases.Influenza virus is positive in 25% or 36% of COPD cases.
|Herpes simplex virus (HSV-1)
||Double-stranded DNA, alpha herpes virus.Causes persistent infection.
||Infects MΦs, DCs through interacting with TLR2/9 to reduce IL-1β and nitric oxide synthase but enhances type I IFN and MCP-1.Reduces lung function and increases mortality.
||HSV-1 is positive in 19% of COPD patients
||Double-stranded DNA, non-enveloped.Causes life-threatening infections of the lower respiratory tract in immune-compromised individuals.Infects bronchial epithelia and integrates the viral E1A gene to the host genome in COPD.
||Infects airway epithelia, persists without detectable replication, and amplifies inflammation in cigarette smoke exposure.Adenovirus early region 1A (E1A) protein interacts with ICAM-1 promoter region in lung epithelial and enhances ICAM-1 expression.E1A protein enhances growth factor production and up-regulates pro-inflammatory signaling to regulate airway remodeling in COPD.Adenovirus 19-kDa protein inhibits HLA class I production and minimizes CD8+ T cell activation.
||Adenovirus is 2.1% positive in 2000 COPD cases.Adenovirus is 7% to 10% positive in exacerbated COPD.
|Epstein-Barr virus (EBV)
||Double-stranded DNA, enveloped, gammaherpesvirus.Infects 95% world population.Interacts with CD21 on B cells and Ephrin receptor A2 on epithelial cells for cell entry.
||Inhibits antigen presentation.Likely increases GM-CSF in monocytes to inhibit monocytes from maturation for antigen presentation, maintain pro-inflammatory function, and promote neutrophils migration from the blood.
||EBV infection increases in COPD.
|Human immunodeficiency virus (HIV)
||Positive-sense, single-stranded, enveloped RNA virus, genus lentivirus, and family retroviridae.∼35 million people live with HIV.Enters the airway epithelium through breaking down cell junctions.Infects MΦs by binding of viral gp120 to CCR5 or CXCR4 and infects CD4+ T cells by binding of viral gp120 to CD4.
||Increases inflammatory cytokines IL-6 and CRP, but not IL-8 or TNF-α.Infects monocytes and MΦs to produce circulating sCD163 and sCD14 as monocyte markers which are associated with severe inflammation and high risk of radiographic emphysema.Circulating endothelin-1 is a biomarker for airflow obstruction in HIV+ individuals.HIV+ COPD shows a high frequency of activated CD8+ T cells in blood and BALF and high activated alveolar MΦs to produce IFNγ.HIV+ emphysema shows a low frequency of CD4+ cells and CD4+/CD8+ T cells, but a high level of sCD14.
||HIV is positive in 2% to 37% cases of emphysema or airflow obstruction.25% HIV+ individuals have COPD.6.8% to 21.0% HIV+ individuals show COPD.26% HIV+ smokers show airflow obstruction.
|Human coronavirus (HCoV)
||Positive-sense, single-stranded, enveloped RNA virus.150 serotypes were divided into alpha, beta, and gamma coronavirus.HCoV is positive in 15% of adult patients diagnosed as common colds.
||Binds to ICAM-1 for cell entry.Alpha-coronavirus-229E isolate binds CD13.Alpha-coronavirus-NL63 binds ACE2.
||HCoV is positive in 4.1% of 2000 COPD cases and is linked to COPD exacerbation.
|Severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2
||SARS-CoV binds ACE2.SARS-CoV-2 uses ACE2, CD26, CD147, and TMPRSS2 as cellular receptors.[51,52]
||SARS-CoV infects cells and is released from cells through endosomal fusion.SARS-CoV and SARS-CoV-2 induce acute lung inflammation, respiratory syndromes, and mortality, as associated with pre-existing COPD.ACE2 expression level high on the bronchial epithelial cells in overweight COPD patients.
||A higher risk of more severe COVID-19 is shown in COPD patients at a relative risk of 1.88, or at a much higher odds ratio (OR) of 5.69.
ACE2: Angiotensin-converting enzyme 2; BALF: Bronchoalveolar lavage fluid; CCL5: CC chemokine ligand-5; CCR: C-C chemokine receptor; COPD: Chronic obstructive pulmonary disease; CRP: C-reactive protein; CXCL10: Chemokine (C-X-C motif) ligand 10; CXCR: C-X-C chemokine receptor; DCs: Dendritic cells; GM-CSF: Granulocyte-macrophage colony-stimulating factor; gp120: HIV envelope glycoprotein; HA: Hemagglutinin; HLA: Human leukocyte antigen; ICAM-1: Intercellular adhesion molecule 1; IFN: Interferon; IL: Interleukin; MΦs: Macrophages; MCP-1: Monocyte chemoattractant protein 1; NA: Neuraminidase; NF-κB: Nuclear factor κ light chain enhancer of activated B cells; PRR: Pattern recognition receptor; RANTES: Regulated on activation, normal T cell expressed and secreted; sCD163: Soluble CD163; sCD14: Soluble CD14; TLR: Toll-like receptor; TMPRSS2: Transmembrane protease, serine 2; TNF-α: Tumor necoris factor-α.
Host-pathogen interactions and innate immune responses in respiratory viral infections and COPD involve airway epithelial cells, stromal cells, and innate immune cells[9–11] as major components forming the activation (input) and effector (output) arms of T cell immunity. Various inflammatory mediators produced by these cells, such as circulating cytokines, chemokines, small molecular mediators, and reactive oxygen species (ROS), are up-regulated to damage airway tissue structures and lung function, eventually reducing respiratory capacity and inducing severe clinical symptoms. As a result, these innate responses will enhance mucus production, disrupt mucociliary clearance and physical integrity of the epithelial barrier, and mediate immune cell migration in the airway. Two major categories of innate molecules critically regulate T cell responses in viral infection and inflammation. First, pattern recognition receptors are important host receptors to interact with pathogen-associated molecular patterns (PAMPs) from viruses to initiate the production of inflammatory mediators for immune regulation. For example, endocytic toll-like receptor (TLR) 3 and TLR7–9 bind viral PAMPs to initiate signaling cascades and activate various transcription factors to regulate cytokine production. Specifically, transcription factors interferon (IFN) regulatory factor (IRF) 3 and IRF7 regulate the production of type I interferons, while transcription factors activator protein 1 and nuclear factor κB mediate the production of pro-inflammatory cytokines.[56,57] Second, cytokines and chemokines produced by innate cells in viral infections further display a broad effector function, such as regulating the pathogenesis mediated by airway epithelia, recruiting other hematopoietic cells, and promoting peptide antigen presentation for T cell activation. For example, chemokine (C-X-C motif) ligand (CXCL) 1/growth regulated oncogene-α, CXCL5/epithelial-derived neutrophil-activating peptide 78, and CXCL8/interleukin (IL)-8 attract neutrophils and monocytes to lung tissues. CXCL9 (monokine induced by IFN-γ), CXCL10 (IFN-γ-induced protein 10 kDa or IP-10), and CXCL11 (interferon-inducible T cell α-chemoattractant) attract type 1 helper T (Th1) cells and cytotoxic T cells to lung tissues. Moreover, interferon production is known to up-regulate the expression of human leukocyte antigen (HLA) class I proteins and co-stimulatory molecules on APCs, such as monocytes, MΦs, and dendritic cells (DCs), for T cell activation.
T Cell Responses in Respiratory Viral Infections and COPD
T cells can be activated at least by three mechanisms, antigen presentation, co-stimulation or co-inhibition, and cytokine stimulation.[59,60] Antigen presentation defines the specificity of T cell responses to viral peptides presented by viral-infected cells. For example, the intracellular infection of influenza viruses stimulates the presentation of viral peptides by either HLA class I proteins to CD8+ T cells or HLA class II proteins to CD4+ T cells. Co-stimulation and co-inhibition involve cell contact-based molecular interactions between APCs and T cells, for example, the interaction of CD80 or CD86 molecules on APCs with CD28 molecule on T cells for the stimulation of T cell responses or with cytotoxic T lymphocyte-associated antigen 4 protein on T cells for the inhibition of T cell responses. Cytokine stimulation has been most often studied and discovered in respiratory inflammation. There are many examples of cytokines contributing to T cell activation and the regulation of lung inflammation. For example, IL-33, a cytokine of the IL-1 family, can be released from epithelial cells to interact with cell surface receptor suppression of tumorigenicity 2 (ST2) to stimulate ST2+CD4+ T cells and other ST2+ immune cells for the induction of steroid-resistant type 2 inflammation. In addition to conventional T cells, unconventional T cells can be activated at the early time of primary infections, such as the responses of natural killer (NK) T cells and mucosal-associated invariant T cells.[59,60,64] After 2 to 4 weeks of infection, conventional T cells expand clonally and accumulate in infection sites to induce anti-viral immune responses.
Whether T cell responses contribute to the pathogenesis of COPD or lung inflammation is an intriguing and challenging question for further investigations. As a proof of concept, T cells transferred from cigarette smoke-exposed mice are sufficient to cause lung tissue inflammation and destruction in immunodeficient recipient mice without cigarette smoke exposure. Although cigarette smoke-exposed mice do not represent COPD, the transferrable T cell-mediated lung pathology may be implicated in COPD, since COPD patients show the oligoclonal expansion of CD4+ T cells. Particularly, the CD4+ T cell subsets with specific autoreactivity to elastin antigens induce T cell proliferation and cytokine production in COPD, demonstrating the pathogenicity of autoreactive CD4+ T cells. CD8+ T cells can be stimulated by intracellular microbial infections, such as viral-infected cells in viral-induced pneumonia. It is critical to understand how viral-specific CD8+ T cells are different from or similar to the “persistently activated” cytotoxic CD8+ T cells as a large population of lymphocytes in the airway of COPD. These persistently activated CD8+ T cells are considered contributors to COPD pathogenesis because their abundance is positively associated with COPD progression and reduced value of forced expiratory volume in 1 second (FEV1) in smokers.
CD8+ T cells
In respiratory viral infections, infected DCs and MΦs migrate from lung tissues to the draining lymph nodes or mucosal-associated lymphoid tissues to activate CD8+ T cells by presenting antigenic viral peptides, the costimulatory interaction of surface molecules, and the stimulation of innate cytokines. Activated CD8+ T cells emerge and fluctuate in tracheal aspirates of individuals within the first 10 days upon the onset of respiratory symptoms in the “common cold” infections of HRV, RSV, human coronavirus, or influenza A virus (IAV). Similarly, primary H1N1 IAV infection in rhesus monkey brings activated CD8+ T cells (not necessary to be antigen-specific) to appear in blood and lung tissues on days 5 to 7 and peak on days 7 to 10 post-inoculation [Figure 1]. Reinfection of H1N1 speeds up the appearance of CD8+ T cells in the lung as early as day 2 post-inoculation with a peak on days 4 to 7. The antigen-specific CD8+ T cells stained with the matched HLA class I proteins and predicted RSV peptides emerge during the first week upon the onset of symptoms, peak in the second week, and gradually disappear in the eighth week. Reinfection of RSV will stimulate a spike of tetramer+ CD8+ T cells for 2 weeks and then maintain at a lower level. Results demonstrate that antigen-specific CD8+ T cells undergo the contraction of effector CD8+ T cells and the differentiation of a memory subset that remains within the lung. In terms of tissue tropism, the RSV- and IAV-specific CD8+ T cells were enriched in the lung with less frequency in the blood, facilitating anti-viral effector and memory responses in infected tissues.
In addition to CD8+ T cells isolated from human tracheal aspirates, CD8+ T cells are more accessible from other sources, such as bronchoalveolar lavage fluid (BALF) and blood to test their responses. Peptides from RSV, IAV, or HRV similarly activate blood CD8+ T cells to produce IFN-γ, tumor necrosis factor-α (TNF-α), and IL-2. Activated CD8+ T cells from individuals with “common cold” viral infections express various activation markers [Figure 2], including pan-leukocyte marker CD11a, IL-2 receptor α (CD25), an inhibitory receptor CD94/NK group 2 member A, activation markers CD44, CD38, human leukocyte antigen DR-locus (HLA-DR), and a proliferation marker Ki-67, together with reduced expression of lymphoid homing receptor CD62-ligand (L-selectin). Activated CD8+ T cells particularly display cytolytic effector responses to provide immune defense against intracellular viral infection [Figure 2]. The surface up-regulation of lysosomal-associated membrane protein-1 (LAMP1 or CD107a) is a cytolytic marker of CD8+ T cell degranulation for the secretion of perforins and granzymes, which together punctuate the membrane of viral-infected cells and kill viruses. Activated CD8+ T cells also produce abundant IFN-γ and TNF-α cytokines to facilitate the cytolytic immune responses by enhancing the intracellular viral-killing mechanisms, such as the generation of ROS.
Intensive studies using adoptive transfer or depletion of activated CD8+ T cells in the mouse system demonstrated the protection of clonal and polyclonal CD8+ T cells to reduce the titers of infected RSV and IAV. Limited human studies also established the role of CD8+ T cells in eliminating respiratory viruses. Experimental infection of RSV in human adults demonstrates a correlation between the number of pre-existing viral-specific CD8+ T cells in airways and a reduced viral load in the nasal cavity and bronchial brushings. Human adults infected with influenza virus similarly display an association between CD8+ T cell cytolytic activity and the clearance of viral shedding in nasal washes by showing that a low IFN-γ+ CD8+ T cell frequency is associated with higher viral titers in H7N9 IAV infection. Multiple mechanisms have been demonstrated in CD8+ T cells to play a cytolytic effector function to clear viral infections. In addition to the cytolytic function mediated by perforins and granzymes, CD8+ T cells can further induce cell death through the cell contact-dependent interaction between CD95 (Fas) and CD95L (FasL) that leads to the apoptosis of virally infected cells for viral clearance [Figure 2], as demonstrated in RSV infection. Moreover, cell contact-dependent interaction can be further mediated by TNF-related apoptosis-inducing ligand (TRAIL) on CD8+ T cells with TRAIL-R1/R2 (death receptor [DR]4/5) on viral-infected cells.
Factors determining the differentiation of memory subsets from naïve precursors remain poorly understood. Chemokine receptors CC chemokine receptor-5 (CCR5) and C-X-C chemokine receptor (CXCR) 5 appear to be involved in this decision-making process after influenza virus infection in mice. CCR5−/−CXCR3−/− CD8+ T cells cannot be fully activated and further contract after viral clearance, supporting the chemokine-directed localization of T cells within infected tissues is critical for antigen encounter, activation, differentiation, and memory formation of CD8+ T cells. A naive (CD45RA) or memory (CD45RO) marker combined with a chemokine receptor CCR7 for lymphoid tissue trafficking or a molecule CD27 for co-stimulation are generally used to label different subsets of memory T cells in humans. Briefly, CD45RA+ CCR7+ labels naïve CD8+ T cells; CD45RA− CCR7+ labels central memory CD8+ T (TCM) cells; CD45RA− CCR7− labels effector memory CD8+ T (TEM) cells; and CD45RA+ CCR7− labels terminally differentiated effector memory CD8+ T (TEMRA) cells. In RSV infection, viral-specific memory CD8+ T cells typically enrich with the TEM subset that expresses a high level of CD27, CD28, and CCR5, and low CD62L, allowing rapid reactivation in lung tissues [Figure 2]. Recently, tissue-resident memory was used to describe tissue-resident memory T (TRM) cells that localize in regional tissues and rapidly respond to infections. In RSV or IAV infection, induced TRM cells are considered to localize in the lung parenchyma, along the wall of large airways, in tissues surrounding bronchioles and alveoli, airway lumen, but not in the lung-draining lymph nodes that are for TCM cells. The generation of TRM cells in influenza and RSV vaccinations through an intranasal route rather than a systemic pathway interestingly supports the tissue residency of TRM cells. Phenotypically, RSV-specific TRM cells expressing high CD69 and CD103 (αE subunit in the integrin αEβ7 molecules) in human BALF are different from CD8+ T cells in the blood, CD8+ T cells newly trafficked to lung tissues, or TEM cells primarily surrounding blood vessels or within the vasculature tissues.
Viral-specific CD8+ T cells can persist for several months and years post-infection, such as upon the infection of RSV or severe acute respiratory syndrome (SARS) viruses, although a speedy declination of viral-specific memory CD8+ T cells appears in the elderlies with RSV infection. Upon encountering the same or cross-reactive viral pathogens in reinfection, memory CD8+ T cells rapidly expand [Figure 3] to produce effector cytokines and cytolytic molecules, including IFN-γ, TNF-α, and granzymes, for viral clearance.[84,85] As essential frontline defenders, TRM cells can more rapidly expand in situ for cytokine production and effector responses before the recruitment of circulating memory CD8+ T cells, as demonstrated in mice with IAV infection. CXCR3 and CCR5 are critical for memory CD8+ T cell expansion upon reinfection, supporting the important roles of chemokine-mediated migration.
Multiple vaccination studies, such as vaccination using CD8+ T cell epitopes against RSV, mediate the reduction or clearance of lung viral titers following RSV challenge. Memory CD8+ T cells are usually known to protect against the infection of the same subtype of viruses. Moreover, the protection against the infection of heterosubtypic viruses has been interestingly evidenced for IAV vaccination. IAV is known for antigenic drifting by mutating residues in surface hemagglutinin (HA) and neuraminidase (NA) proteins, leading to the loss of protection from prior vaccination using a different IAV subtype. However, cross-subtype protection can be mediated by memory CD8+ T cells, as demonstrated in H1N1 IAV-immunized mice for controlling a lethal challenge of H2N2 IAV without inducing anti-H2N2 neutralizing antibodies or controlling a challenge of the highly virulent subtype of H7N7 without anti-H7N7 neutralizing antibodies [Figure 3A]. This cross-subtype protection mediated by memory CD8+ T cells has been shown in non-human primates as well [Figure 3A]. In humans, cross-subtype protection against respiratory viral infection has been similarly implied and demonstrated. For example, CD8+ T cell responses induced by unattenuated live IAV intranasally are cross-reactive to different subtypes of IAV, while antibody responses remain specific for each IAV subtype. Pre-existing H3N2-specific memory CD8+ T cells are associated with reduced viral shedding in later pandemic H1N1 IAV infection [Figure 3A]. Moreover, pre-existing RSV-specific memory CD8+ T cells in experimental RSV infections correlate with a lower symptom score. Therefore, to improve the efficacy and protection relies on a better understanding of the pathway of vaccination and infection, conservation of subtype antigens, and the induction of antigen-specific CD8+ TRM cells, as in IAV infections[85,91] and animal studies.[70,89]
As an opposite side of protection, a potential risk is that cytolytic CD8+ T cells may be able to exacerbate COPD through inducing cytolysis[92,93] and cell death.[8,30,77] Moreover, can TNF-α and IFN-γ cytokines produced by activated CD8+ T cells promote inflammatory pathologies, such as in RSV or IAV infection? Different from anti-viral protection mediated by activated CD8+ T cells upon IAV or SARS vaccination,[91,95] these CD8+ T cells potentially induce immunopathology. However, both cytokines can be systematically produced in abundant innate immune cells, so further investigation with controls on cell type- and subset-specific cytokine production is required to address the role of CD8+ T cell-derived cytokines in a cytokine storm or inflammation. Another hypothesis is that suboptimal activation of CD8+ T cells upon viral infection likely leads to relatively lower enhancement of CD69 expression and minimal contraction of activated CD8+ T cells through Fas-mediated apoptosis. Thus, the accumulation of several suboptimally activated CD8+ T cells may lead to pro-inflammatory responses through cytolysis and inflammatory cell recruitment in lung tissues, as consistent with an increased number but a suboptimal function of CD8+ T cells in COPD.
CD8+ T cells in COPD
The frequency of CD8+ T cells in the lung tissue and blood of COPD patients is high and inversely associated with FEV1 value.[92,96] The CD8+ T cell subsets in COPD are also functionally altered in cytolytic gene expression and inflammatory cytokine production. In comparison to control subjects without COPD or without viral infection, CD8+ T cells from COPD patients with low FEV1 values show enhanced messenger RNA (mRNA) expression of perforin and granzyme B but not FasL upon in vitro stimulation of IL-18 or IL-15. IL-17-expressing CD8+ T cells increase in the lungs and blood of COPD patients, likely contributing to the pathogenesis of COPD.[97,98] Using an ex vivo infection model, CD8+ T cells from COPD human subjects are defective in response to the influenza virus (H3N2). The CD8+ T cells from COPD patients show reduced anti-viral cytotoxicity and highly express PD-1 protein, contributing to the defective immune defense reactivity of CD8+ T cells. Moreover, CD8+ T cell dysfunction in COPD is also shown with downregulated CD247 (CD3ζ) expression. This is consistent with the known mechanisms by which various viruses escape immune recognition and antigen presentation for T cell activation.
CD4+ T cells
CD4+ T cells play important heterogeneous regulatory roles in anti-viral immune responses and inflammations. CD4+ T cells regulate B cell differentiation and antibody production against viral infection, the activation of viral-specific CD8+ T cells, and the activation and recruitment of innate immune cells [Figure 4]. Interestingly, CD4+ T cells can similarly mediate cytolytic functions to enhance host resistance to various viruses, including IAV infection.
In comparison to CD8+ T cells, similar mechanisms but different molecules activate CD4+ T cells. Specifically, CD4+ T cells use HLA class II protein-mediated antigen presentation for activation and cytokine stimulation to differentiate helper or regulatory CD4+ T cells [Figure 4]. In addition to viral peptide presentation, innate cytokine stimulation is quite unique for CD4+ T cell activation [Figure 4A]. Different sets of cytokines facilitate the differentiation of various helper CD4+ T cell subsets, each of which is controlled by various master transcription factors [Figure 4]. These cytokines and transcription factors are essential to facilitate the differentiation of Th1, Th2, Th17, regulatory T (Treg), and follicular helper (Tfh) CD4+ T cells [Figure 4B], as detailed in the elegant review. For example, in HRV infection, the HRV-derived proteinase 2A stimulates monocyte-derived dendritic cells to further activate CD4+ T cells for the differentiation of Th1 and Th2 cells.
Effector responses and protection
Activated CD4+ Th1 cells express multiple cytokines, such as IFN-γ, TNF-α, and IL-2 [Figure 4B], and contribute to anti-viral immune responses. It is known that IFN-γ acts on phagocytes, such as monocytes, MΦs, and DCs, to suppress viral replication and up-regulate HLA protein expression, which reversely enhances T cell activation as in an indirect positive feedback loop. Differently, IL-2 induces the expansion and differentiation of T cells using direct positive feedback. CD4+ T cells can further regulate CD8+ T cell activation and function through stimulating DCs for the expression of CD40 co-stimulatory molecule to interact with CD40 ligand (CD40L) on CD8+ T cells and the production of cytokine IL-12 to stimulate CD8+ T cells [Figure 4B]. CD4+ T cells alone can be hyperpolarized by IL-2 and antigens to express perforin and granzymes as cytolytic T cells to lyse viral-infected target cells and clear the influenza virus [Figure 4C]. For B cell responses, CD4+ T cells use the Tfh cell subset featured with the expression of surface CXCR5 and signature transcription factor B-cell lymphoma 6 (Bcl6) to regulate B cell differentiation, antibody production, and antibody class switching[107,108] [Figure 4C]. Tfh cells mainly localize in the B cell follicles of secondary lymphoid organs and can be detected in non-lymphoid lung tissues. Furthermore, Treg cells are imperative in respiratory viral infections by suppressing over-stimulated inflammatory responses and tissue damage mediated by other innate and adaptive immune components, and potentially inhibiting anti-viral immune responses. Different cytokines critically regulate Treg expansion and function. For example, the pro-inflammatory cytokines IL-6 or type I IFN impairs Treg activity in acute viral infections, including coronavirus disease 2019, SARS, and IAV infections. In contrast, T cell cytokine IL-2 promotes Treg expansion and response to inhibit inflammatory responses by producing IL-10 and transforming growth factor-beta (TGF-β).[110,111]
Effector responses and exacerbation
Potentially functioned as a negative side in anti-viral immune responses, Th2 and Th17 subsets of CD4+ T cells differentiate in different respiratory virus infections [Figure 4B]. Although RSV infection elicits protective Th1 and cytolytic T cells, RSV infection also stimulates Th2 responses to release IL-4, IL-5, and IL-13 for the recruitment of eosinophils, which further induce lung tissue damage. For example, F and G protein of RSV may interestingly skew CD4+ T cells to Th1 or Th2 subsets, respectively. Overall outcomes of excess Th2 responses are known to further induce elevated airway hyperactivity, airflow difficulty, and lung function deterioration. Th17 cells produce IL-17 and IL-22 and recruit neutrophils. Unsurprisingly, IL-17 production contributes to the influx of neutrophils, inflammation, and tissue damage, as in RSV infection. Moreover, IL-17 can bind to interleukin-17 receptor (IL-17R) to inhibit the anti-viral function of CD8+ T cells.
In respiratory viral infections, memory CD4+ T cells often express an activated phenotype, have a lower frequency than memory CD8+ T cells, and contract within a few months [Figure 1].[117,118] Similarly, memory CD4+ T cells can be maintained and ready for reactivation during secondary infections [Figure 4D]. The reactivated CD4+ TEM cells rapidly express cytokines and surface co-stimulatory receptors such as CD40L, to regulate antigen presentation, B cell differentiation, inflammatory cell recruitment, and CD8+ T cell responses. Memory CD4+ T cells generated upon respiratory viral infections are antigen-specific in memory responses for regulating B cell activation. IAV-specific memory CD4+ T cells are heterogeneous in peptide antigen specificities and functional outcomes, by responding to peptides derived from variable surface HA and NA proteins, and conserved nucleoprotein (NP) and matrix 1 proteins [Figure 3B]. Regarding antigen specificity, CXCR5+ Tfh-like cells from the circulation of healthy adults were enriched for clonal reactivity to more variable HA protein than the conserved NP, while other CD4+ T cells without CXCR5 expression were preferentially reactive to conserved NP. Further tests show that HA-specific CD4+ T cells (Tfh or Tfh-like cells) potentially regulate neutralizing antibody responses, which are more likely elicited by the surface variable protein HA. Through interacting with the viral-infected or viral protein-endocytosed B cells, CD4+ T cells are activated and differentiated by recognizing the peptides derived from the surface-exposed HA proteins to regulate antibody production against this source protein [Figure 3B].
CD4+ T cells in COPD
Autoreactive CD4+ T cells occur in human COPD. The CD4+ T cells isolated from the blood and lung samples of COPD patients with emphysema are shown with a Th1 phenotype, which correlates with emphysema severity. Anti-elastin antibodies are detected in individuals with emphysema. Unlike the protection induced by antigen-specific CD4+ T cells in influenza viral infections, helper CD4+ T cells responding to elastin peptides from patients with emphysema may be detrimental. In this elegant study, blockade of major histocompatibility complex class II molecules inhibits CD4+ T-cell responses to elastin peptides, confirming their antigen specificity. Activated CD4+ T cells in emphysematous lungs exhibit a predominantly Th1 effector phenotype and secrete CXCL10. The fold increase of IFN-γ and IL-10 produced by CD4+ T cells is associated with disease severity. In addition to a Th1 cytokine secretion pattern (such as IFN-γ production) from most studies with COPD clinical specimens,[120,121] Th2 responses (with IL-4 production) were also reported in different studies complexed by various confounding factors and disease severity. As major cells regulating autoimmune and inflammatory responses, Treg cells detected with a CD4+CD25hi phenotype often reduce in COPD. However, CD4+ T cells labeled with transcription factor Foxp3 can increase in lung tissues, potentially due to Foxp3 expression in effector and memory human T cell subsets as well. Following the reduction of CD25, CD4+CD25−Foxp3+ T cells appear to lose Treg-associated molecules and functions. Therefore, functional and cytokine measurements are essential to characterize Treg cells. For example, decreased TGF-β+ and IL-10+ cells in small airways, and impaired suppressive function are relevant to persistent inflammation in COPD.[126,127]
T cells interact with innate immune components to receive input signals for activation and deliver effector responses as outputs in respiratory viral infections and COPD. Viral-infected APCs stimulate T cells to differentiate into various subsets [Figures 2 and 4] in lung tissues and reversely regulate innate cells to orchestrate immune responses for inhibiting viral infections or exacerbating inflammations. Each cellular or molecular factor has unique features to interplay in this infection and inflammation microenvironment. In particular, the peptide-reactive T cells are characterized by antigen specificity, receptor-ligand recognition, response to non-self, persistence at a low frequency, precise response to stimulation, kinetically diverse, clearing viruses, memory to primary stimulation, regulation of inflammation, and apoptosis to minimize damage. These T cell characteristics allow effective anti-viral immune responses and precise protection during various stages of viral infections. Ideally, T cells can be regulated to provide bidirectional protection by enhancing hyporeactive and suppressing hyperreactive immunity. Several molecules and cellular subsets, including TRM cells, Treg, memory CD8+ T cells, and viral peptide antigens, can be targeted for future vaccine or therapeutic development.
However, streamlined pathways for the activation and effector function of different immune cells remain mostly unknown and unpredictable in the context of cellular interactions, imposing challenges in designing vaccination and therapeutic strategies. Understanding the following fundamental aspects in T cell responses will significantly forward our knowledge and methodology to induce immune protection against respiratory viral infections and chronic inflammations represented by COPD. For example, can and how peptide specificity lead to different effector functions, or can peptide antigen specificity of CD4+ and CD8+ T cells predict protection? Can CD4+ Tfh cells that regulate B cell differentiation and antibody production link the peptide specificity of Tfh cells with antibody specificity? As initiated in the studies of IAV-stimulated CD4+ T cell responses, experiments in mice support that memory CD4+ T cells responding to NP peptides cannot recall the production of anti-HA antibodies [Figure 3B]. Notably, memory CD4+ T cells responding to HA peptides regulate an enhanced antibody production to HA protein, leading to lower viral titers in the lungs. Similar questions can be raised to understand viral-specific CD8+ T cells. Moreover, how can we predict the protection or exacerbation of T cell and innate immune responses in viral infections to balance viral clearance and excessive inflammation? How do the investigations on viral virulence and invasion pathways provide knowledge to understand immunological processes that potentially exacerbate COPD? Precise and comprehensive understandings of the activation and regulation pathways of various CD4+ and CD8+ T cells in respiratory viral infections and COPD are fundamental to provide optimal targets for designing intervention and therapeutic strategies for disease control.
This work was supported by grants from the National Key Research and Development Program of China (No. 2018YFC1313602), Major International (Regional) Joint Research Project (No. 81820108001), National Natural Science Foundation of China (No. 81670029), Jiangsu Key Principal Investigator of Medicine (No. ZDRCA2016018), Project 333 for Cultivation of Young and Middle-aged Leading Talents (No. BRA2019078), Jiangsu Key Program of Social Development (No. BE2015651), and Nanjing Key Project of Science and Technology (No. 2019060002) (to Linfu Zhou), and the National Institute of Environmental Health Sciences (No. ES006096), Center for Environmental Genetics, National Institute of Allergy and Infectious Diseases (No. AI115358), and American Lung Association (No. IA-629987) (to Shouxiong Huang).
Conflicts of interest
1. Ruuskanen O, Lahti E, Jennings LC, Murdoch DR. Viral pneumonia. Lancet
2011; 377:1264–1275. doi: 10.1016/S0140-6736(10)61459-6.
2. Friedlander AL, Lynch D, Dyar LA, Bowler RP. Phenotypes of chronic obstructive pulmonary disease. COPD
2007; 4:355–384. doi: 10.1080/15412550701629663.
3. Barker BL, Brightling CE. Phenotyping the heterogeneity of chronic obstructive pulmonary disease. Clin Sci (Lond)
2013; 124:371–387. doi: 10.1042/CS20120340.
4. Burden of COPD. Geneva: World Health Organization, 2020. Available from: https://www.who.int/respiratory/copd/burden/en/
. [Accessed July 10, 2020].
5. Toelle BG, Xuan W, Bird TE, Abramson MJ, Atkinson DN, Burton DL, et al. Respiratory symptoms and illness in older Australians: the Burden of Obstructive Lung Disease (BOLD) study. Med J Aust
2013; 198:144–148. doi: 10.5694/mja11.11640.
6. Kim D, Chen Z, Zhou LF, Huang SX. Air pollutants and early origins of respiratory diseases. Chronic Dis Transl Med
2018; 4:75–94. doi: 10.1016/j.cdtm.2018.03.003.
7. Li T, Hu R, Chen Z, Li Q, Huang S, Zhu Z, et al. Fine particulate matter (PM2.5): the culprit for chronic lung diseases in China. Chronic Dis Transl Med
2018; 4:176–186. doi: 10.1016/j.cdtm.2018.07.002.
8. Barnes PJ. Immunology of asthma and chronic obstructive pulmonary disease. Nat Rev Immunol
2008; 8:183–192. doi: 10.1038/nri2254.
9. Linden D, Guo-Parke H, Coyle PV, Fairley D, McAuley DF, Taggart CC, et al. Respiratory viral infection: a potential “missing link” in the pathogenesis of COPD. Eur Respir Rev
2019; 28:180063doi: 10.1183/16000617.0063-2018.
10. Ritchie AI, Farne HA, Singanayagam A, Jackson DJ, Mallia P, Johnston SL. Pathogenesis of viral infection in exacerbations of airway disease. Ann Am Thorac Soc
2015; 12: (Suppl 2): S115–S132. doi: 10.1513/AnnalsATS.201503-151AW.
11. Hewitt R, Farne H, Ritchie A, Luke E, Johnston SL, Mallia P. The role of viral infections in exacerbations of chronic obstructive pulmonary disease and asthma. Ther Adv Respir Dis
2016; 10:158–174. doi: 10.1177/1753465815618113.
12. Beasley V, Joshi PV, Singanayagam A, Molyneaux PL, Johnston SL, Mallia P. Lung microbiology and exacerbations in COPD. Int J Chron Obstruct Pulmon Dis
2012; 7:555–569. doi: 10.2147/COPD.S28286.
13. Seemungal T, Harper-Owen R, Bhowmik A, Moric I, Sanderson G, Message S, et al. Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med
2001; 164:1618–1623. doi: 10.1164/ajrccm.164.9.2105011.
14. Zwaans WA, Mallia P, van Winden ME, Rohde GG. The relevance of respiratory viral infections in the exacerbations of chronic obstructive pulmonary disease—a systematic review. J Clin Virol
2014; 61:181–188. doi: 10.1016/j.jcv.2014.06.025.
15. Britto CJ, Brady V, Lee S, Dela Cruz CS. Respiratory viral infections in chronic lung diseases. Clin Chest Med
2017; 38:87–96. doi: 10.1016/j.ccm.2016.11.014.
16. Jafarinejad H, Moghoofei M, Mostafaei S, Salimian J, Azimzadeh Jamalkandi S, Ahmadi A. Worldwide prevalence of viral infection in AECOPD patients: a meta-analysis. Microb Pathog
2017; 113:190–196. doi: 10.1016/j.micpath.2017.10.021.
17. McManus TE, Marley AM, Baxter N, Christie SN, O’Neill HJ, Elborn JS, et al. Respiratory viral infection in exacerbations of COPD. Respir Med
2008; 102:1575–1580. doi: 10.1016/j.rmed.2008.06.006.
18. Rohde G, Wiethege A, Borg I, Kauth M, Bauer TT, Gillissen A, et al. Respiratory viruses in exacerbations of chronic obstructive pulmonary disease requiring hospitalisation: a case-control study. Thorax
2003; 58:37–42. doi: 10.1136/thorax.58.1.37.
19. Wedzicha JA. Role of viruses in exacerbations of chronic obstructive pulmonary disease. Proc Am Thorac Soc
2004; 1:115–120. doi: 10.1513/pats.2306030.
20. Ledford RM, Patel NR, Demenczuk TM, Watanyar A, Herbertz T, Collett MS, et al. VP1 sequencing of all human rhinovirus serotypes: insights into genus phylogeny and susceptibility to antiviral capsid-binding compounds. J Virol
2004; 78:3663–3674. doi: 10.1128/jvi.78.7.3663-3674.2004.
21. Korpi-Steiner NL, Valkenaar SM, Bates ME, Evans MD, Gern JE, Bertics PJ. Human monocytic cells direct the robust release of CXCL10 by bronchial epithelial cells during rhinovirus infection. Clin Exp Allergy
2010; 40:1203–1213. doi: 10.1111/j.1365-2222.2010.03546.x.
22. Schneider D, Ganesan S, Comstock AT, Meldrum CA, Mahidhara R, Goldsmith AM, et al. Increased cytokine response of rhinovirus-infected airway epithelial cells in chronic obstructive pulmonary disease. Am J Respir Crit Care Med
2010; 182:332–340. doi: 10.1164/rccm.200911-1673OC.
23. Ghildyal R, Dagher H, Donninger H, de Silva D, Li X, Freezer NJ, et al. Rhinovirus infects primary human airway fibroblasts and induces a neutrophil chemokine and a permeability factor. J Med Virol
2005; 75:608–615. doi: 10.1002/jmv.20315.
24. Mohan A, Chandra S, Agarwal D, Guleria R, Broor S, Gaur B, et al. Prevalence of viral infection detected by PCR and RT-PCR in patients with acute exacerbation of COPD: a systematic review. Respirology
2010; 15:536–542. doi: 10.1111/j.1440-1843.2010.01722.x.
25. Greenberg SB. Update on human rhinovirus and coronavirus infections. Semin Respir Crit Care Med
2016; 37:555–571. doi: 10.1055/s-0036-1584797.
26. Krzyzaniak MA, Zumstein MT, Gerez JA, Picotti P, Helenius A. Host cell entry of respiratory syncytial virus involves macropinocytosis followed by proteolytic activation of the F protein. PLoS Pathog
2013; 9:e1003309doi: 10.1371/journal.ppat.1003309.
27. Liu D, Chen Q, Zhu H, Gong L, Huang Y, Li S, et al. Association of respiratory syncytial virus toll-like receptor 3-mediated immune response with COPD exacerbation frequency. Inflammation
2018; 41:654–666. doi: 10.1007/s10753-017-0720-4.
28. Groskreutz DJ, Monick MM, Powers LS, Yarovinsky TO, Look DC, Hunninghake GW. Respiratory syncytial virus induces TLR3 protein and protein kinase R, leading to increased double-stranded RNA responsiveness in airway epithelial cells. J Immunol
2006; 176:1733–1740. doi: 10.4049/jimmunol.176.3.1733.
29. Dou D, Revol R, Östbye H, Wang H, Daniels R. Influenza A virus cell entry, replication, virion assembly and movement. Front Immunol
2018; 9:1581doi: 10.3389/fimmu.2018.01581.
30. Ellis GT, Davidson S, Crotta S, Branzk N, Papayannopoulos V, Wack A. TRAIL+ monocytes and monocyte-related cells cause lung damage and thereby increase susceptibility to influenza-Streptococcus pneumoniae coinfection. EMBO Rep
2015; 16:1203–1218. doi: 10.15252/embr.201540473.
31. Kruger P, Saffarzadeh M, Weber AN, Rieber N, Radsak M, von Bernuth H, et al. Neutrophils: between host defence, immune modulation, and tissue injury. PLoS Pathog
2015; 11:e1004651doi: 10.1371/journal.ppat.1004651.
32. McNamee LA, Harmsen AG. Both influenza-induced neutrophil dysfunction and neutrophil-independent mechanisms contribute to increased susceptibility to a secondary Streptococcus pneumoniae infection. Infect Immun
2006; 74:6707–6721. doi: 10.1128/IAI.00789-06.
33. Tan WC, Xiang X, Qiu D, Ng TP, Lam SF, Hegele RG. Epidemiology of respiratory viruses in patients hospitalized with near-fatal asthma, acute exacerbations of asthma, or chronic obstructive pulmonary disease. Am J Med
2003; 115:272–277. doi: 10.1016/s0002-9343(03)00353-x.
34. Lucinda N, Figueiredo MM, Pessoa NL, Santos BS, Lima GK, Freitas AM, et al. Dendritic cells, macrophages, NK and CD8+ T lymphocytes play pivotal roles in controlling HSV-1 in the trigeminal ganglia by producing IL1-beta, iNOS and granzyme B. Virol J
2017; 14:37doi: 10.1186/s12985-017-0692-x.
35. Morimoto K, Gosselink J, Kartono A, Hogg JC, Hayashi S, Ogawa E. Adenovirus E1A regulates lung epithelial ICAM-1 expression by interacting with transcriptional regulators at its promoter. Am J Physiol Lung Cell Mol Physiol
2009; 296:L361–371. doi: 10.1152/ajplung.90331.2008.
36. Kasuga I, Hogg JC, Paré PD, Hayashi S, Sedgwick EG, Ruan J, et al. Role of genetic susceptibility to latent adenoviral infection and decreased lung function. Respir Med
2009; 103:1672–1680. doi: 10.1016/j.rmed.2009.05.008.
37. Ogawa E, Elliott WM, Hughes F, Eichholtz TJ, Hogg JC, Hayashi S. Latent adenoviral infection induces production of growth factors relevant to airway remodeling in COPD. Am J Physiol Lung Cell Mol Physiol
2004; 286:L189–197. doi: 10.1152/ajplung.00315.2002.
38. Kokturk N, Bozdayi G, Yilmaz S, Doğan B, Gulbahar O, Rota S, et al. Detection of adenovirus and respiratory syncytial virus in patients with chronic obstructive pulmonary disease: exacerbation versus stable condition. Mol Med Rep
2015; 12:3039–3046. doi: 10.3892/mmr.2015.3681.
39. Hoshino Y, Katano H, Zou P, Hohman P, Marques A, Tyring SK, et al. Long-term administration of valacyclovir reduces the number of Epstein-Barr virus (EBV)-infected B cells but not the number of EBV DNA copies per B cell in healthy volunteers. J Virol
2009; 83:11857–11861. doi: 10.1128/JVI.01005-09.
40. Jabs WJ, Paulsen M, Wagner HJ, Kirchner H, Klüter H. Analysis of Epstein-Barr virus (EBV) receptor CD21 on peripheral B lymphocytes of long-term EBV- adults. Clin Exp Immunol
1999; 116:468–473. doi: 10.1046/j.1365-2249.1999.00912.x.
41. Chen J, Sathiyamoorthy K, Zhang X, Schaller S, Perez White BE, Jardetzky TS, et al. Ephrin receptor A2 is a functional entry receptor for Epstein-Barr virus. Nat Microbiol
2018; 3:172–180. doi: 10.1038/s41564-017-0081-7.
42. McManus TE, Marley AM, Baxter N, Christie SN, Elborn JS, O’Neill HJ, et al. High levels of Epstein-Barr virus in COPD. Eur Respir J
2008; 31:1221–1226. doi: 10.1183/09031936.00107507.
43. Fitzpatrick ME, Nouraie M, Gingo MR, Camp D, Kessinger CJ, Sincebaugh JB, et al. Novel relationships of markers of monocyte activation and endothelial dysfunction with pulmonary dysfunction in HIV-infected persons. AIDS
2016; 30:1327–1339. doi: 10.1097/QAD.0000000000001092.
44. Attia EF, Akgün KM, Wongtrakool C, Goetz MB, Rodriguez-Barradas MC, Rimland D, et al. Increased risk of radiographic emphysema in HIV is associated with elevated soluble CD14 and nadir CD4. Chest
2014; 146:1543–1553. doi: 10.1378/chest.14-0543.
45. Morris A, Alexander T, Radhi S, Lucht L, Sciurba FC, Kolls JK, et al. Airway obstruction is increased in pneumocystis-colonized human immunodeficiency virus-infected outpatients. J Clin Microbiol
2009; 47:3773–3776. doi: 10.1128/JCM.01712-09.
46. Fitzpatrick ME, Kunisaki KM, Morris A. Pulmonary disease in HIV-infected adults in the era of antiretroviral therapy. AIDS
2018; 32:277–292. doi: 10.1097/QAD.0000000000001712.
47. Lalloo UG, Pillay S, Mngqibisa R, Abdool-Gaffar S, Ambaram A. HIV and COPD: a conspiracy of risk factors. Respirology
2016; 21:1166–1172. doi: 10.1111/resp.12806.
48. Triplette M, Crothers K, Attia EF. Non-infectious pulmonary diseases and HIV. Curr HIV/AIDS Rep
2016; 13:140–148. doi: 10.1007/s11904-016-0313-0.
49. Makinson A, Hayot M, Eymard-Duvernay S, Quesnoy M, Raffi F, Thirard L, et al. High prevalence of undiagnosed COPD in a cohort of HIV-infected smokers. Eur Respir J
2015; 45:828–831. doi: 10.1183/09031936.00154914.
50. Falsey AR, Walsh EE, Hayden FG. Rhinovirus and coronavirus infection-associated hospitalizations among older adults. J Infect Dis
2002; 185:1338–1341. doi: 10.1086/339881.
51. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell
2020; 181:271–280.e8. doi: 10.1016/j.cell.2020.02.052.
52. Radzikowska U, Ding M, Tan G, Zhakparov D, Peng Y, Wawrzyniak P, et al. Distribution of ACE2, CD147, CD26, and other SARS-CoV-2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hypertension, and COVID-19 risk factors. Allergy
2020; 75:2829–2845. doi: 10.1111/all.14429.
53. Higham A, Singh D. Increased ACE2 expression in bronchial epithelium of COPD patients who are overweight. Obesity (Silver Spring)
2020; 28:1586–1589. doi: 10.1002/oby.22907.
54. Ananthakrishnan AN. Detecting and treating Clostridium difficile infections in patients with inflammatory bowel disease. Gastroenterol Clin North Am
2012; 41:339–353. doi: 10.1016/j.gtc.2012.01.003.
55. Lippi G, Henry BM. Chronic obstructive pulmonary disease is associated with severe coronavirus disease 2019 (COVID-19). Respir Med
2020; 167:105941doi: 10.1016/j.rmed.2020.105941.
56. Shah M, Anwar MA, Kim JH, Choi S. Advances in antiviral therapies targeting toll-like receptors. Expert Opin Investig Drugs
2016; 25:437–453. doi: 10.1517/13543784.2016.1154040.
57. Zhou LF, Yin KS. Toll-like receptors: function and roles in asthma. Chin Med J
2004; 117:1709–1715. doi: 10.3760/cma.j.issn.0366-6999.2004.11.120.
58. Fensterl V, Sen GC. Interferons and viral infections. Biofactors
2009; 35:14–20. doi: 10.1002/biof.6.
59. Sharma M, Zhang S, Niu L, Lewinsohn DM, Zhang X, Huang S. Mucosal-associated invariant T cells
develop an innate-like transcriptomic program in anti-mycobacterial responses. Front Immunol
2020; 11:1136doi: 10.3389/fimmu.2020.01136.
60. Huang S. Targeting innate-like T cells
in tuberculosis. Front Immunol
2016; 7:594doi: 10.3389/fimmu.2016.00594.
61. Alegre ML, Frauwirth KA, Thompson CB. T-cell regulation by CD28 and CTLA-4. Nat Rev Immunol
2001; 1:220–228. doi: 10.1038/35105024.
62. Branchett WJ, Lloyd CM. Regulatory cytokine function in the respiratory tract. Mucosal Immunol
2019; 12:589–600. doi: 10.1038/s41385-019-0158-0.
63. Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity
2005; 23:479–490. doi: 10.1016/j.immuni.2005.09.015.
64. Hansen TH, Huang S, Arnold PL, Fremont DH. Patterns of nonclassical MHC antigen presentation. Nat Immunol
2007; 8:563–568. doi: 10.1038/ni1475.
65. Motz GT, Eppert BL, Sun G, Wesselkamper SC, Linke MJ, Deka R, et al. Persistence of lung CD8 T cell oligoclonal expansions upon smoking cessation in a mouse model of cigarette smoke-induced emphysema. J Immunol
2008; 181:8036–8043. doi: 10.4049/jimmunol.181.11.8036.
66. Lee SH, Goswami S, Grudo A, Song LZ, Bandi V, Goodnight-White S, et al. Antielastin autoimmunity in tobacco smoking-induced emphysema. Nat Med
2007; 13:567–569. doi: 10.1038/nm1583.
67. Chen K, Kolls JK. T cell-mediated host immune defenses in the lung. Annu Rev Immunol
2013; 31:605–633. doi: 10.1146/annurev-immunol-032712-100019.
68. Saetta M, Turato G, Maestrelli P, Mapp CE, Fabbri LM. Cellular and structural bases of chronic obstructive pulmonary disease. Am J Respir Crit Care Med
2001; 163:1304–1309. doi: 10.1164/ajrccm.163.6.2009116.
69. Heidema J, Rossen JW, Lukens MV, Ketel MS, Scheltens E, Kranendonk ME, et al. Dynamics of human respiratory virus-specific CD8+ T cell responses in blood and airways during episodes of common cold. J Immunol
2008; 181:5551–5559. doi: 10.4049/jimmunol.181.8.5551.
70. Weinfurter JT, Brunner K, Capuano SV 3rd, Li C, Broman KW, Kawaoka Y, et al. Cross-reactive T cells
are involved in rapid clearance of 2009 pandemic H1N1 influenza virus in nonhuman primates. PLoS Pathog
2011; 7:e1002381doi: 10.1371/journal.ppat.1002381.
71. de Bree GJ, van Leeuwen EM, Out TA, Jansen HM, Jonkers RE, van Lier RA. Selective accumulation of differentiated CD8+ T cells
specific for respiratory viruses in the human lung. J Exp Med
2005; 202:1433–1442. doi: 10.1084/jem.20051365.
72. Hogan RJ, Usherwood EJ, Zhong W, Roberts AA, Dutton RW, Harmsen AG, et al. Activated antigen-specific CD8+ T cells
persist in the lungs following recovery from respiratory virus infections. J Immunol
2001; 166:1813–1822. doi: 10.4049/jimmunol.166.3.1813.
73. Schmidt ME, Varga SM. The CD8 T cell response to respiratory virus infections. Front Immunol
2018; 9:678doi: 10.3389/fimmu.2018.00678.
74. Jozwik A, Habibi MS, Paras A, Zhu J, Guvenel A, Dhariwal J, et al. RSV-specific airway resident memory CD8+ T cells
and differential disease severity after experimental human infection. Nat Commun
2015; 6:10224doi: 10.1038/ncomms10224.
75. McMichael AJ, Gotch FM, Noble GR, Beare PA. Cytotoxic T-cell immunity to influenza. N Engl J Med
1983; 309:13–17. doi: 10.1056/NEJM198307073090103.
76. Wang ZF, Wan YM, Qiu CL, Quiñones-Parra S, Zhu Z, Loh L, et al. Recovery from severe H7N9 disease is associated with diverse response mechanisms dominated by CD8+ T cells
. Nat Commun
2015; 6:6833doi: 10.1038/ncomms7833.
77. Aung S, Rutigliano JA, Graham BS. Alternative mechanisms of respiratory syncytial virus clearance in perforin knockout mice lead to enhanced disease. J Virol
2001; 75:9918–9924. doi: 10.1128/Jvi.75.20.9918-9924.2001.
78. Kohlmeier JE, Reiley WW, Perona-Wright G, Freeman ML, Yager EJ, Connor LM, et al. Inflammatory chemokine receptors regulate CD8(+) T cell contraction and memory generation following infection. J Exp Med
2011; 208:1621–1634. doi: 10.1084/jem.20102110.
79. Mahnke YD, Brodie TM, Sallusto F, Roederer M, Lugli E. The who's who of T-cell differentiation: human memory T-cell subsets. Eur J Immunol
2013; 43:2797–2809. doi: 10.1002/eji.201343751.
80. Zens KD, Chen JK, Farber DL. Vaccine-generated lung tissue-resident memory T cells
provide heterosubtypic protection to influenza infection. JCI Insight
2016; 1:e85832doi: 10.1172/jci.insight.85832.
81. Morabito KM, Ruckwardt TR, Redwood AJ, Moin SM, Price DA, Graham BS. Intranasal administration of RSV antigen-expressing MCMV elicits robust tissue-resident effector and effector memory CD8+ T cells
in the lung. Mucosal Immunol
2017; 10:545–554. doi: 10.1038/mi.2016.48.
82. Chen H, Hou J, Jiang X, Ma S, Meng M, Wang B, et al. Response of memory CD8+ T cells
to severe acute respiratory syndrome (SARS) coronavirus in recovered SARS patients and healthy individuals. J Immunol
2005; 175:591–598. doi: 10.4049/jimmunol.175.1.591.
83. de Bree GJ, Heidema J, van Leeuwen EM, van Bleek GM, Jonkers RE, Jansen HM, et al. Respiratory syncytial virus-specific CD8+ memory T cell responses in elderly persons. J Infect Dis
2005; 191:1710–1718. doi: 10.1086/429695.
84. Flynn KJ, Belz GT, Altman JD, Ahmed R, Woodland DL, Doherty PC. Virus-specific CD8+ T cells
in primary and secondary influenza pneumonia. Immunity
1998; 8:683–691. doi: 10.1016/s1074-7613(00)80573-7.
85. McMaster SR, Wilson JJ, Wang H, Kohlmeier JE. Airway-resident memory CD8 T cells
provide antigen-specific protection against respiratory virus challenge through rapid IFN-γ production. J Immunol
2015; 195:203–209. doi: 10.4049/jimmunol.1402975.
86. Slütter B, Van Braeckel-Budimir N, Abboud G, Varga SM, Salek-Ardakani S, Harty JT. Dynamics of influenza-induced lung-resident memory T cells
underlie waning heterosubtypic immunity. Sci Immunol
2017; 2:eaag2031doi: 10.1126/sciimmunol.aag2031.
87. Lee S, Stokes KL, Currier MG, Sakamoto K, Lukacs NW, Celis E, et al. Vaccine-elicited CD8+ T cells
protect against respiratory syncytial virus strain A2-line19F-induced pathogenesis in BALB/c mice. J Virol
2012; 86:13016–13024. doi: 10.1128/JVI.01770-12.
88. Schulman JL, Kilbourne ED. Induction of partial specific heterotypic immunity in mice by a single infection with influenza A virus. J Bacteriol
1965; 89:170–174. doi: 10.1128/JB.89.1.170-174.1965.
89. Christensen JP, Doherty PC, Branum KC, Riberdy JM. Profound protection against respiratory challenge with a lethal H7N7 influenza A virus by increasing the magnitude of CD8(+) T-cell memory. J Virol
2000; 74:11690–11696. doi: 10.1128/jvi.74.24.11690-11696.2000.
90. Hayward AC, Wang L, Goonetilleke N, Fragaszy EB, Bermingham A, Copas A, et al. Natural T cell-mediated protection against seasonal and pandemic influenza. Results of the Flu Watch Cohort Study. Am J Respir Crit Care Med
2015; 191:1422–1431. doi: 10.1164/rccm.201411-1988OC.
91. Wu T, Hu Y, Lee YT, Bouchard KR, Benechet A, Khanna K, et al. Lung-resident memory CD8 T cells
(TRM) are indispensable for optimal cross-protection against pulmonary virus infection. J Leukoc Biol
2014; 95:215–224. doi: 10.1189/jlb.0313180.
92. O'Shaughnessy TC, Ansari TW, Barnes NC, Jeffery PK. Inflammation in bronchial biopsies of subjects with chronic bronchitis: inverse relationship of CD8+ T lymphocytes with FEV1. Am J Respir Crit Care Med
1997; 155:852–857. doi: 10.1164/ajrccm.155.3.9117016.
93. Freeman CM, Han MK, Martinez FJ, Murray S, Liu LX, Chensue SW, et al. Cytotoxic potential of lung CD8(+) T cells
increases with chronic obstructive pulmonary disease severity and with in vitro stimulation by IL-18 or IL-15. J Immunol
2010; 184:6504–6513. doi: 10.4049/jimmunol.1000006.
94. Ostler T, Davidson W, Ehl S. Virus clearance and immunopathology by CD8(+) T cells
during infection with respiratory syncytial virus are mediated by IFN-gamma. Eur J Immunol
2002; 32:2117–2123. doi: 10.1002/1521-4141(200208)32:8<2117::AID-IMMU2117>3.0.CO;2-C.
95. Channappanavar R, Fett C, Zhao J, Meyerholz DK, Perlman S. Virus-specific memory CD8 T cells
provide substantial protection from lethal severe acute respiratory syndrome coronavirus infection. J Virol
2014; 88:11034–11044. doi: 10.1128/JVI.01505-14.
96. Wang J, Li X, Hou WJ, Dong LX, Cao J. Endothelial function and T-lymphocyte subsets in patients with overlap syndrome of chronic obstructive pulmonary disease and obstructive sleep apnea. Chin Med J
2019; 132:1654–1659. doi: 10.1097/CM9.0000000000000312.
97. Chang Y, Nadigel J, Boulais N, Bourbeau J, Maltais F, Eidelman DH, et al. CD8 positive T cells
express IL-17 in patients with chronic obstructive pulmonary disease. Respir Res
2011; 12:43doi: 10.1186/1465-9921-12-43.
98. Xu WH, Hu XL, Liu XF, Bai P, Sun YC. Peripheral Tc17 and Tc17/interferon-γ cells are increased and associated with lung function in patients with chronic obstructive pulmonary disease. Chin Med J
2016; 129:909–916. doi: 10.4103/0366-6999.179798.
99. McKendry RT, Spalluto CM, Burke H, Nicholas B, Cellura D, Al-Shamkhani A, et al. Dysregulation of antiviral function of CD8(+) T cells
in the chronic obstructive pulmonary disease lung. Role of the PD-1-PD-L1 axis. Am J Respir Crit Care Med
2016; 193:642–651. doi: 10.1164/rccm.201504-0782OC.
100. Grundy S, Plumb J, Lea S, Kaur M, Ray D, Singh D. Down regulation of T cell receptor expression in COPD pulmonary CD8 cells. PLoS One
2013; 8:e71629doi: 10.1371/journal.pone.0071629.
101. Hansen TH, Bouvier M. MHC class I antigen presentation: learning from viral evasion strategies. Nat Rev Immunol
2009; 9:503–513. doi: 10.1038/nri2575.
102. Bevan MJ. Helping the CD8(+) T-cell response. Nat Rev Immunol
2004; 4:595–602. doi: 10.1038/nri1413.
103. Brown DM, Lee S, Garcia-Hernandez Mde L, Swain SL. Multifunctional CD4 cells expressing gamma interferon and perforin mediate protection against lethal influenza virus infection. J Virol
2012; 86:6792–6803. doi: 10.1128/JVI.07172-11.
104. Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations (∗). Annu Rev Immunol
2010; 28:445–489. doi: 10.1146/annurev-immunol-030409-101212.
105. Singh M, Lee SH, Porter P, Xu C, Ohno A, Atmar RL, et al. Human rhinovirus proteinase 2A induces TH1 and TH2 immunity in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol
2010; 125:1369–1378.e2. doi: 10.1016/j.jaci.2010.02.035.
106. Schoenberger SP, Toes RE, van der Voort EI, Offringa R, Melief CJ. T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature
1998; 393:480–483. doi: 10.1038/31002.
107. Qi H. T follicular helper cells in space-time. Nat Rev Immunol
2016; 16:612–625. doi: 10.1038/nri.2016.94.
108. Boyden AW, Legge KL, Waldschmidt TJ. Pulmonary infection with influenza A virus induces site-specific germinal center and T follicular helper cell responses. PLoS One
2012; 7:e40733doi: 10.1371/journal.pone.0040733.
109. Arpaia N, Green JA, Moltedo B, Arvey A, Hemmers S, Yuan S, et al. A distinct function of regulatory T cells
in tissue protection. Cell
2015; 162:1078–1089. doi: 10.1016/j.cell.2015.08.021.
110. Ballesteros-Tato A, León B, Graf BA, Moquin A, Adams PS, Lund FE, et al. Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity
2012; 36:847–856. doi: 10.1016/j.immuni.2012.02.012.
111. Shevach EM. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity
2009; 30:636–645. doi: 10.1016/j.immuni.2009.04.010.
112. Graham BS, Bunton LA, Wright PF, Karzon DT. Role of T lymphocyte subsets in the pathogenesis of primary infection and rechallenge with respiratory syncytial virus in mice. J Clin Invest
1991; 88:1026–1033. doi: 10.1172/JCI115362.
113. Singh SR, Dennis VA, Carter CL, Pillai SR, Moore EG. Respiratory syncytial virus recombinant F protein (residues 255-278) induces a helper T cell type 1 immune response in mice. Viral Immunol
2007; 20:261–275. doi: 10.1089/vim.2007.0008.
114. Singanayagam A, Joshi PV, Mallia P, Johnston SL. Viruses exacerbating chronic pulmonary disease: the role of immune modulation. BMC Med
2012; 10:27doi: 10.1186/1741-7015-10-27.
115. Bystrom J, Al-Adhoubi N, Al-Bogami M, Jawad AS, Mageed RA. Th17 lymphocytes in respiratory syncytial virus infection. Viruses
2013; 5:777–791. doi: 10.3390/v5030777.
116. Mukherjee S, Lindell DM, Berlin AA, Morris SB, Shanley TP, Hershenson MB, et al. IL-17-induced pulmonary pathogenesis during respiratory viral infection and exacerbation of allergic disease. Am J Pathol
2011; 179:248–258. doi: 10.1016/j.ajpath.2011.03.003.
117. Cauley LS, Cookenham T, Miller TB, Adams PS, Vignali KM, Vignali DA, et al. Cutting edge: virus-specific CD4+ memory T cells
in nonlymphoid tissues express a highly activated phenotype. J Immunol
2002; 169:6655–6658. doi: 10.4049/jimmunol.169.12.6655.
118. DiPiazza A, Richards KA, Knowlden ZA, Nayak JL, Sant AJ. The role of CD4 T cell memory in generating protective immunity to novel and potentially pandemic strains of influenza. Front Immunol
2016; 7:10doi: 10.3389/fimmu.2016.00010.
119. Bingaman AW, Patke DS, Mane VR, Ahmadzadeh M, Ndejembi M, Bartlett ST, et al. Novel phenotypes and migratory properties distinguish memory CD4 T cell subsets in lymphoid and lung tissue. Eur J Immunol
2005; 35:3173–3186. doi: 10.1002/eji.200526004.
120. Majori M, Corradi M, Caminati A, Cacciani G, Bertacco S, Pesci A. Predominant TH1 cytokine pattern in peripheral blood from subjects with chronic obstructive pulmonary disease. J Allergy Clin Immunol
1999; 103:458–462. doi: 10.1016/s0091-6749(99)70471-9.
121. Hodge G, Nairn J, Holmes M, Reynolds PN, Hodge S. Increased intracellular T helper 1 proinflammatory cytokine production in peripheral blood, bronchoalveolar lavage and intraepithelial T cells
of COPD subjects. Clin Exp Immunol
2007; 150:22–29. doi: 10.1111/j.1365-2249.2007.03451.x.
122. Barcelo B, Pons J, Fuster A, Sauleda J, Noguera A, Ferrer JM, et al. Intracellular cytokine profile of T lymphocytes in patients with chronic obstructive pulmonary disease. Clin Exp Immunol
2006; 145:474–479. doi: 10.1111/j.1365-2249.2006.03167.x.
123. Hou J, Sun Y. Role of regulatory T cells
in disturbed immune homeostasis in patients with chronic obstructive pulmonary disease. Front Immunol
2020; 11:723doi: 10.3389/fimmu.2020.00723.
124. Kmieciak M, Gowda M, Graham L, Godder K, Bear HD, Marincola FM, et al. Human T cells
express CD25 and Foxp3 upon activation and exhibit effector/memory phenotypes without any regulatory/suppressor function. J Transl Med
2009; 7:89doi: 10.1186/1479-5876-7-89.
125. Wu JH, Zhou M, Jin Y, Meng ZJ, Xiong XZ, Sun SW, et al. Generation and immune regulation of CD4+CD25-Foxp3+ T cells
in chronic obstructive pulmonary disease. Front Immunol
2019; 10:220doi: 10.3389/fimmu.2019.00220.
126. Sales DS, Ito JT, Zanchetta IA, Annoni R, Aun MV, Ferraz LFS, et al. Regulatory T-cell distribution within lung compartments in COPD. COPD
2017; 14:533–542. doi: 10.1080/15412555.2017.1346069.
127. Tan DB, Fernandez S, Price P, French MA, Thompson PJ, Moodley YP. Impaired function of regulatory T-cells in patients with chronic obstructive pulmonary disease (COPD). Immunobiology
2014; 219:975–979. doi: 10.1016/j.imbio.2014.07.005.