The Effect of FOXP3+ Regulatory T Cells on Infectious and Inflammatory Diseases : Infectious Microbes & Diseases

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The Effect of FOXP3+ Regulatory T Cells on Infectious and Inflammatory Diseases

Bai, Yakun1,2,3,4; Gao, Fang5; Li, Dan4; Ji, Suyuan4; Zhang, Shuijun1,2,3; Guo, Wenzhi1,2,3; Li, Bin4

Editor(s): Wang, Fudi

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Infectious Microbes & Diseases 3(4):p 187-197, December 2021. | DOI: 10.1097/IM9.0000000000000070
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Abstract

Introduction

The immune system is critical for maintaining homeostasis by distinguishing between “self” and “non-self” and eliminating “non-self” components. Fighting against infections is of great importance since pathogens have developed considerable mechanisms of immune escape during evolution. FOXP3+ regulatory T cells (Tregs) refer to one of T cell subtypes that express CD4, CD25, and transcription factor forkhead box P3 (FOXP3). Their normal function essentially impacts the dynamic regulation of human immune homeostasis. The development and function of Tregs display a close association with the physiological process of infectious diseases. Tregs can mitigate tissue damage caused by inflammation and suppress the body's immune response to pathogens in viral, bacterial, protozoan, worm, and fungal infections. The present review focuses on the development, physiological functions, and mechanisms of FOXP3+ Tregs, as well as the latest progress in research concerned with the prevention and treatment of infectious diseases.

Development of FOXP3+ Tregs

Since Tregs have different sources, they can be divided into several subgroups. One of the subgroups refers to thymus-derived Tregs (tTregs). Another subgroup is the peripheral-derived Tregs (pTregs). Both tTregs and pTregs are considered as natural Tregs (nTregs) compared with induced Tregs (iTregs).

Thymic development of natural FOXP3+ Tregs

Consistent with all T cells, nTregs are differentiated in the thymus by progenitor cells from the bone marrow. nTregs take up 5%–10% of CD4+ T cells in the periphery, and their physiological function is of crucial significance for the maintenance of immune homeostasis.1 In mice, nTregs migrate from the thymus to the periphery 3 days after birth. Mice undergoing thymectomy can develop severe autoimmune diseases.2 T cell receptor (TCR)-signaling is critical to thymus development of nTregs.3 Moreover, considerable T cell surface receptor co-stimulating molecules [eg, CD28, interleukin (IL)-2 receptor, transforming growth factor-β (TGF-β) receptor, and glucocorticoid-induced tumor necrosis factor-related receptor (GITR)] significantly regulate the development of nTregs.4,5,6 Furthermore, the development of nTregs is regulated by thymic stromal cell signaling. Natural FOXP3+ thymic T cells primarily exist in the thymic medulla.7 Myeloid thymic epithelial cells and dendritic cells (DCs) promote nTregs to be differentiated.8

Peripheral generation of induced FOXP3+ Tregs

As revealed from the results of in vitro and in vivo experiments, iTregs can be generated by inducing the expression of FOXP3 in natural CD4+ T cells. Specifically, under TGF-β signaling, in vitro antigen stimulation of natural T cells induces iTreg production.9 During TGF-β–dependent induction of Tregs in vitro, differentiation of iTregs can be prevented in the presence of IL-6 signaling, and joint stimulation of TGF-β and IL-6 can promote naive CD4+ T cells to be differentiated into T helper type 17 (Th17) cells.10 IL-2 signaling is capable of inducing naive CD4+ T cells to be transformed into FOXP3+ Tregs and suppressing these cells from being differentiated into Th17 cells.11 Moreover, retinoic acid, a metabolite of vitamin A, can suppress IL-6-signal–induced Th17 differentiation.12 In the presence of TGF-β signaling, retinoic acid promotes naive T cells to be differentiated into FOXP3+ Tregs. Specific to mice, the extracellular signals required for the development of iTregs and nTregs may not be identical. The development of nTregs requires TCR stimulation of intermediate affinity autoantigen peptide, while the development of iTregs corresponds to weak TCR stimulation and the response to foreign antigens in the peripheral environment.11 Furthermore, co-stimulating receptor CD28 signaling is not required for iTreg differentiation, since iTregs can be induced in vitro with CD28 deficiency (Figure 1).13

F1
Figure 1:
The development and differentiation of regulatory T cells (Tregs). Tregs differentiated in the thymus are called tTregs. The pTregs are naive T cells differentiated into Treg cells in the periphery under TGF-β and IL-2 stimulation. Tregs induced in vitro are named iTreg cells. IL: interleukin; TGF: transforming growth factor-β.

The functions of Tregs

When pathogenic microorganisms invade the body, both innate and adaptive immune systems will induce a range of responses to eliminate pathogens. If the immune response is excessively active, it may also cause tissue damage while removing the pathogen. Tregs protect the host from autoimmune responses by suppressing overstimulated immune responses. Tregs suppress immune responses through different mechanisms, including suppressive cytokines, cytolysis, metabolic breakdown, and DC mature or function adjusted responses. Tregs suppress effector T cells (Teff cells) and natural killer cells by secreting immunosuppressive cytokines (eg, IL-10, IL-35, and TGF-β).14 Tregs express high levels of IL-2 receptors to competitively bind IL-2 and cause IL-2 deficiency in the microenvironment. This process prevents other T cells from binding to IL-2 and affects T cell activation and proliferation.15 The synergistic suppressive molecule cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) expressed on Tregs can bind with high affinity to CD80 and CD86 molecules on the surface of antigen-presenting cells (APCs) to initiate suppressive signals.1 Tregs regulate the activity of APCs and Teff cells by suppressing receptors that include GITR, CTLA-4, lymphocyte-activation gene 3 (LAG-3), and programmed death-1 (PD-1).16 Tregs promote apoptosis, and the secondary messenger cyclic AMP (cAMP) is transferred to Teff cells based on interstitial junctions, so the immune function of Teff cells may be directly suppressed.17

FOXP3 is required for Treg function, especially for its suppressive activity

Disruption of FOXP3 expression by Tregs results in inflammation, autoimmunity, and metabolic dysregulation. FOXP3 gene mutations in mice lead to severe systemic autoimmune inflammatory diseases (eg, scurfy phenotype).18 Mutations in human FOXP3 are closely related with immune dysregulation, enteropathy, polyendocrinopathy, and X-linked (IPEX) syndrome.19 FOXP3 governs the transcription of target genes, inducing genes including CD25, CTLA-4, GITR, CD103, and tumor necrosis factor receptor superfamily member 18 (TNFRSF18), and suppressing genes including IL-2, Interferon-γ, IL-4 and protein tyrosine phosphatase non-receptor type 22 (PTPN22), thereby causing immunosuppression.

Post-translational modifications (PTMs) of proteins link cellular signals to the functional properties

The FOXP3 function is directly regulated by multiple PTMs occurring in response to various external stimuli. Phosphorylation is involved in the intracellular stability, interactions, and localization of proteins. Kaempferol can decrease PIM1-mediated FOXP3 phosphorylation at S422.20 The Pim-2 kinase can phosphorylate FOXP3, thereby leading to reduced suppressive functions of Tregs. The amino-terminal domain of FOXP3 is modified at several sites by the Pim-2 kinase, which leads to altered expression of proteins related to Treg functions and increased Treg lineage stability.21 Ubiquitin-specific protease (USP) 7 and USP21 can deubiquitinate and stabilize FOXP3.22 In a previous study, it was demonstrated that USP4 physically interacts with interferon regulatory factor 8 (IRF8) function via a K48-linked deubiquitinase, which stabilizes IRF8 protein levels in Tregs. Deficiency of USP4 alleviates the suppressive functions of Tregs.23 USP21 stabilizes FOXP3 proteins by mediating its deubiquitination, while maintaining the expression of Treg signature genes.24 By removing K48-linked ubiquitin modifications, USP44 stabilizes and deubiquitinates FOXP3 in cooperation with USP7.25 Since both ubiquitination and acetylation are restricted to lysine residues, acetylation may compete with poly-ubiquitination to stabilize FOXP3. Two acetyltransferases, Tip60 and p300, are reported as enzymes that are responsible for FOXP3 acetylation.26,27 The histone acetyltransferase Tip60 can be recruited to the repressor domain of FOXP3 and regulate FOXP3-mediated suppression of IL-2 expression.28,29,30 Moreover, p300 can interact with FOXP3 and acetylate FOXP3 directly, and ectopic expression of p300 may strengthen FOXP3 stability. FOXP3 can be demethylated at positions R27, R51, and R146, which was discovered by conducting mass spectrometry analysis. An Arginine to Lysine point mutation leads to defective suppressive functions in human CD4+ T cells. Pharmacological suppression of protein arginine methyl transferase 5 (PRMT5) also reduces human Treg functions and suppresses the methylation of FOXP3.31

Protein O-GlcNAcylation is critical to lineage stability and effector functions in Tregs. Moreover, through TCR-activated PTM by O-linked N-Acetylglucosamine (O-GlcNAc), FOXP3 can be stabilized, and signal transducer and activator of transcription 5 (STAT5) can be activated, so these critical signaling pathways can be integrated.16

Tregs in infectious diseases

FOXP3+ Tregs are capable of regulating the intensity of pathological responses mediated by immune effector cells. The main function of Tregs is to respond to the relevant signals of tissue damage to reduce the damage. However, in the process of the body being infected by exogenous pathogens, the regulation of FOXP3+ Treg in the pathological process of chronic infections will cause failure of timely elimination of pathogens and longterm treatment of infectious diseases (Table 1).

Table 1 - The role of Tregs in various infectious diseases
Type Microorganism Disease The changes and roles of Tregs The important genes References
Parasite Leishmania Leishmaniasis In infected dogs, T cells decreased while IL-10+ Tregs increased in the spleen.Tregs delay the splenic pathology and inhibit leukocyte expansion. IL-10TGF-βP110δGalectin-3CCR6CCR5 32–45
Plasmodium Malaria Tregs decrease at acute infection state and in asymptomatic individuals.Tregs increase at chronic malaria infections.Tregs decrease the immune response against infections CTLA-4OX-40IL-10PD-1sFGL2S100A8 46–58
Schistosoma Schistosomiasis Mice deleted IL-4Rα showed exacerbation of immune response during Schistosoma mansoni infections.Tregs produce IL-10 and TGF-β during infections.Tregs create immune suppression environment. IL-4RIL-10TGF-β 59–66
Virus RSV RSV infection RSV infections cause Tregs to migrate from peripheral blood to the lungs and lymph nodes.RSV nonstructural proteins NS1 inhibit the differentiation of Tregs, while NS2 plays an opposite role.RSV increases the number of local Tregs. TLR4 67–78
SARS-CoV-2 COVID-19 Patients with COVID-19 have lower numbers of Tregs, and the decline was more significant in severe cases. 69–71
HBV Hepatitis B Tregs promote immune escape of HBV and block Tfh response caused by HBV. CCL22 72–74
HCV Hepatitis C Tregs impede the clearance of HCV, produce IL-8 acting on hepatic stellate cells, and limit the extent of fibrosis. CCL17CCL22 75–78
HIV AIDS HIV promotes the development of Tregs by enhancing monocytic myeloid-derived suppressor cells and promotes the differentiation of immature T cells into Tregs through plasmacytoid dendritic cell activation.IL-21 promotes the survival of Tregs and inhibits the apoptosis in HIV infection. IL-21CCR5IDO 79–86
Coxsackie virus A16 enterovirus 71 HFMD Tregs proportion and IL-10 and TGF-β1 levels are decreased. 87–88
Bacteria Listeria monocytogenes Listeriosis Tregs are increased during pregnancy and in transgenic mice. Tregs increase susceptibility to Listeria. 89–95
Mycobacterium tuberculosis Tuberculosis The proliferation of pathogen-specific Tregs are promoted in the initial inflammatory responses, but these cells are actively culled later by IL-12–induced the Th1-cell–promoting transcription factor T-bet.Tregs are associated with human recombinant IL-4, which reduces mycobacterial containment in infected macrophages. 96–101
Helicobacter pylori H. Pylori infectionGastritisGastric cancer H. Pylori regulates migrate of Tregs through up-regulation of CCR6, CXCR1 and CXCR2 in peripheral blood Treg. CCR6-CCL20 102–109
Salmonella TyphoidAcute gastroenteritis In early stages of infections, FOXP3+ Tregs are increased.In late-stage infections, FOXP3+ Tregs are reduced. 110–112
AIDS: acquired immunodeficiency syndrome; COVID-19: coronavirus disease 2019; HBV: hepatitis B virus; HCV: hepatitis C virus; HFMD: hand-foot-and-mouth disease; HIV: human immunodeficiency virus; RSV: respiratory syncytial virus; SARS-CoV-2: respiratory syndrome coronavirus 2; Tregs: regulatory T cells.

Parasitic infections

Leishmania

Leishmania spp. are digenetic protozoan parasites that are transmitted by sand fly bites, and cause a variety of chronic diseases in their animal reservoirs and in susceptible human hosts. Leishmania species have two stages, that is, flagellate promastigotes and nonflagellate amastogotes. The final host cells for Leishmania parasites are macrophages. The survival and division of nonflagellate in macrophages lead to the formation of parasitophorous vacuoles. Subsequently, considerable numbers of macrophages are destroyed. Leishmaniasis refers to a systemic infection of the reticuloendothelial system, which causes both acute infections and lifelong chronic infections of the liver and spleen. Several studies showed that hepatic stellate cells are critical to the incidence of leishmaniasis. For instance, investigation of T cell immunity in dog models indicated that in the intestine, the percentage of CD8+ T cells and macrophage increased while numbers of CD4+ T cells and FOXP3+ Tregs were not influenced in the Leishmania-infected group.32 In infected dogs, the number of T cells decreased while the IL-10+ Tregs increased in the spleen.33 These data suggest that Tregs play important roles during Leishmania infections. The source and function of IL-10 are complicated. Deletion of Tregs in mice indicates that the main functions of FOXP3+ Tregs are delaying the splenic pathology and inhibiting leukocyte expansion during Leishmania infections. Investigation in IL-10 and IL-10R deficient mice suggests that the functions of FOXP3+ Tregs during Leishmania infections are independent of IL-10.34 Furthermore, it has been discovered that the number of FOXP3+ Tregs in the periphery of infected patients is similar to healthy donor and the suppression function and expression of IL-10 are higher in patients.35 The expression levels of IL-10 and TGF-β in plasma have a significant positive correlation with parasite loads.36 Mice with a P110δ gene mutation develop resistance to visceral leishmaniasis, which partially results from a decrease of hepatic stellate cell function to induce and amplify Tregs.37 For Leishmania-infected BALB/c IL-4 knockout and IL-4Rα knockout mice, as impacted by an inherent defect in Th1 differentiation, IL-10– and Treg–mediated suppression does not default to the Th2 pathway. Inconsistent with the extreme susceptibility of BALB/c mice attributed to abnormal Th2 responses, the susceptibility of cure-resistant mice is on account of the imbalance of Tregs that are activated under a continuous Th1 response; in addition, the primary function of Tregs may be to suppress the immunopathology associated with continuous anti-parasite responses in infected tissues.38 According to mice infection models, antigen-iTregs exert an effect on the effector phase of the immune response (ie, controlling immunopathology) and may also delay or prevent healing. After the mouse is cured and the infection is resolved, CD25+Foxp3+ Tregs prevent sterile healing and establish long-term functional immune privilege status in the skin in an IL-10–dependent manner.39 Galectin-3, a glycan-binding protein, has important roles in innate and adaptive immunity. Deficiency of galectin-3 increases the number and function of Tregs in both lymph nodes and infection sites during Leishmania infections. Galectin-3 negatively regulates the expression of CD103 and IL-10 in Tregs.40 CC chemokine receptor 6 (CCR6), a chemokine receptor shared by Th17 and Tregs, guides T cells to the inflamed site. After Leishmania infections, CCR6-deficient mice showed reduced Treg numbers and unchanged Th17 cell numbers in the lymph nodes and developed protective Th1 immune responses, and enhanced Th2 and CD8 cytokine expression.41 Furthermore, the chemokine receptor CCR5 displays an association with the long-term survival of the parasite in the host. CCR5–/– CD4+CD25+ nTregs leads to an increase in the number of parasite-specific CD4+ T cells that synthesize interferon at the site of infection, resulting in a significant decrease in the number of parasites, as well as a strong resistance to infections.42 C-X-C motif chemokine ligand 10 (CXCL10) is also reported to be important in mice infected by Leishmania through regulating IL-10+ Tregs. In vivo experiments indicated that treating Leishmania-infected BALB/c mice with CXCL10 can reduce both the parasite load in the spleen and the numbers of CD25Foxp3IL-10+ cells and FOXP3+ Tregs.43 Some new strategies have been developed to treat visceral leishmaniasis because of limitations of first-line drugs. Ara-LAM, a Toll-like receptor 2 (TLR2) ligand, can induce strong Th1 type immune responses, reduce the expression of IL-10 and TGF-β, and decrease Treg generation and activation in BALB/c mice. Ara-LAM decreases Tregs through suppressing the TGF-β-SMAD pathway and inducing IRF1, which negatively regulates the expression of FOXP3.44 In chronically infected mice models, both the numbers and function of Tregs are impaired. Ehrlich et al. discovered that rIL-2-anti-IL-2 antibody complex treatment can increase Tregs and decrease cytokine responses, which ameliorates lesions and parasite loads.45

Plasmodium

Malaria parasites (Plasmodium spp.) are sporozoan transmitted by anopheles mosquitoes. Malaria is attributed to anopheles bites or input with blood containing the parasite. It is a highly prevalent fatal disease worldwide, and it can cause anemia and brain inflammation. During acute malaria infections, T cell responses and the suppression function of Tregs are impaired.46 As suggested from numerous statistics, chronic malaria can cause significant increases of CD4+FOXP3+ T cells, both in humans and in mice.47,48 Maternal parasitosis can modulate fetal immune development, as it is reported that Plasmodium falciparum infections are associated with elevated CD4+ T cells, and reduced CD8+ T cells and Tregs in the cord blood of infants.49 In asymptomatic individuals, DC cells are increased and Tregs exhibit reduced activation.50 During recurrent malaria episodes, IL-10 levels increase and the numbers of CD4+ T cells and CD8+ T cells are decreased, which indicates that remodeling of the immune response is dependent on repeated exposure to the parasite.51 Tregs act at a critical time window based on CTLA-4, thereby impeding the time-discrete and reducing the potentially therapeutic compliance functional role of protective immune T cells and CTLA-4, thereby limiting antimalarial immunity.52 The number of parasites is positively correlated with the proportion of FOXP3+ Tregs expressing CTLA-4 or OX-40.53Plasmodium vivax infections cause an increase of circulating Treg numbers and expression of PD-1 in Tregs. As revealed from functional analysis, the suppressive function of Tregs is impaired in malaria patients. The expression levels of FOXP3 and Helios of PD-1+ Tregs are lower than that of PD-1 Tregs, and the frequency of T-box transcription factor positive and interferon positive cells is higher than that in PD-1 Tregs.54Plasmodium can induce Tregs to release soluble fibrinogen like protein 2 (sFGL2), manipulating the host innate immune response and immune suppression.55 The plasma levels of IL-10 and S100A8 are high in infected patients, which may correlate with a decreased immune response.56,57 The RNA levels of Annexin-A1 are high in Tregs of patients infected with malaria, which suggests that Annexin-A1 may contribute to the function of Tregs.57 In a C57bl/6 experimental cerebral malaria mouse model, the levels of IL-10–secreting Tregs or IL-10+Foxp3CD4+ T cells were similar to control mice and showed a Treg-associated Th2 response.58

Schistosomiasis

Schistosomiasis (bilharziasis) is a type of disease attributed to parasitic worms. The primary pathological process is the formation of granuloma on account of the eggs deposited in host organs (eg, liver and colon). During the first three weeks of infection in mice, the larval parasites migrate from the skin to the lungs or other organs. Both the number and activation state of Tregs are comparable in lungs, draining lymph nodes, and spleens of mice infected with Schistosoma mansoni. Treg responses are different when infected with different types of parasitic helminths.59 Schmiedel et al. investigated the function of Tregs after treatment with Praziquantel and discovered that the number of Tregs decreased after treatment, while cytokine production remained unchanged.60 Mice deleted for IL-4Rα in Tregs show an exacerbated immune response during S. mansoni infections. IL-4Rα deletion in Tregs results in downregulated FOXP3 protein levels, and noticeably decreased C-X-C motif chemokine receptor 3 (CXCR3), GATA binding protein 3 (GATA3), and B cell lymphoma 2 (Bcl-2) levels, which can impact the migration and accumulation of Tregs in inflamed tissues, as well as the survival of Tregs.61 Generation of IL-10 is generally known as one of the suppression mechanisms of Tregs. The production of IL-10 and TGF-β is promoted significantly in Schistosoma-infected patients.62 In the skin of mice, the production of IL-10 increases after repeated Schistosoma infection compared to a single infection. And IL-10, secreted by both Treg and Teff cells, is required for immune regulation against schistosomiasis.63 As suggested from research on mouse models infected with Schistosoma japonicum, elevated IL-10 levels induce differentiation of Tregs, while reducing their immunosuppressive function. This result may be related to the fact that IL-10 elevates serum levels of TGF-β and downregulates the levels of Treg membrane type combined TGF-β during S. japonicum infections. An identical mechanism has been confirmed in asthma mouse models. Since Tregs are particularly susceptible to nicotinamide adenine dinucleotide (NAD)-induced cell death (NICD), it has been hypothesized that schistosomiasis-degraded NAD facilitates Treg survival to create an immune repressive environment.64 ApoE-deficient mice have higher burdens of adult worms and hepatic eggs and more serious hepatic pathological lesions and hepatic fibrosis than wild-type mice when infected with S. japonicum. Furthermore, ApoE deletion aggrieves the imbalance of Th17/Treg ratios through inducing Th17 cell levels and suppressing Tregs. During this process, the lipid metabolism is dysregulated in ApoE-deficient mice.65 Fucoidan, a polysaccharide mainly extracted from brown marine algae, has been evaluated to treat S. japonicum infections in mouse models. The results showed that fucoidan significantly reduces the hepatic granuloma size and fibrosis responses, which is related to the increase of Tregs and expression levels of IL-10 and TGF-β.66

Viral infections

Viral infections display a close relationship to immune suppression, which is based on the impaired function of lymphocyte antigen presentation and the triggering of T cell subsets. In the process of interacting with the host, viruses exploit a range of ways to eliminate adverse factors, as an attempt to evade attack by the host immune system. On the other hand, the host activates the immune system to monitor and clear viruses. Over the past few years, the activity of Tregs during infections by a variety of viruses has been studied.

Respiratory syncytial virus (RSV)

RSV (syncytial virus for short) is a type of RNA virus belonging to the vice mucus virus family, which most commonly causes infantile viral pneumonia. RVS infections cause interstitial pneumonia and capillary bronchitis. Research revealed that during RSV infections, Tregs and Th17 cells determine the nature of the immune response and the severity of the disease. Tregs rapidly accumulate in the lungs and mediastinal lymph nodes in RSV-infected mice, which demonstrates that RSV infections are likely to cause Tregs to migrate from peripheral blood to the lungs and lymph nodes. Moreover, this result explains why peripheral blood Tregs are reduced during RSV infections.67 NS1 and NS2, two nonstructural RSV proteins can critically impact RSV replication. NS1 is capable of suppressing the differentiation of Tregs, whereas NS2 exerts the opposite effect. Furthermore, the F protein of RSV can specifically bind to TLR4 receptors on the Treg cell surface, thereby further elevating the number of local Tregs.68

Coronavirus disease 2019 (COVID-19)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly pathogenic virus causing COVID-19. This coronavirus is recognized as a type of acute respiratory distress syndrome that seriously endangers global health. In the most severe cases, elevated levels of infection-related biomarkers and inflammatory cytokines were reported. Both the number of total T cells and the number of Tregs decrease significantly during SARS-CoV-2 infections, and the decline was more significant in severe cases.69 Studies suggested that increasing Treg levels may help diminish the severity of viral diseases, especially that of COVID-19.70 According to the clinical response to SARS-CoV-2 infection, the virus affects women less than men since women have higher levels of Tregs than men.71

Hepatitis B virus (HBV)

HBV is the pathogen that causes hepatitis B. It pertains to the hepatitis DNA virus family. HBV mainly causes liver cirrhosis and hepatocellular carcinoma. Treg responses are likely to be either beneficial or detrimental to those infected with HBV and hepatitis C virus (HCV), which is achieved by limiting liver immunopathology or suppressing protective T cell responses, respectively.72 During acute hepatitis, T cells respond to HBV to clear it. During chronic hepatitis B, however, the T cell response to HBV is limited. It has been reported that in HBV-infected livers, TGF-β activity is elevated to downregulate the expression of microRNA-34a, while the production of chemokine C-C motif chemokine 22 (CCL22) is enhanced. CCL22 can recruit Tregs to facilitate immune escape.73 In HBV-infected mice and humans, a follicular helper T cell (Tfh-cell) response to hepatitis B surface antigen is required for HBV clearance, and Tregs block this response. Loss of Treg numbers and suppression of function (with blocking antibody against CTLA-4) restore the Tfh-cell response against hepatitis B surface antigen and clear HBV in mice.74

HCV

HCV is a single plus-stranded RNA virus that can cause hepatitis C. HCV is transmitted via blood or vertical transmission. According to the elevated number and function of CD4+CD25+FOXP3+ Tregs in HCV-infected patients, Tregs are suggested to play a role in impaired viral clearance.75 CD4+FOXP3+ Tregs are identified as an additional intrahepatic source of IL-8 in chronic hepatitis C, acting on hepatic stellate cells.76 In hepatitis C, the virus attracts Tregs to the site of infection by inducing the expressions of CCL17 and CCL22 chemokines.77 It has been experimentally demonstrated that considerable CD4+FOXP3+ Tregs that are highly activated and differentiated are localized to the infiltrated chronic HCV-infected liver and may cause the extent of fibrosis to be limited. It is therefore suggested that CD4+FOXP3+ Tregs critically limit collateral damage by suppressing excessive HCV-induced immune activation.78

Human immunodeficiency virus (HIV)

HIV is a virus that attacks the human immune system by targeting the most important CD4+ T lymphocytes. HIV destroys numerous CD4+ T cells and makes the human body lose immune functions. As revealed from clinical manifestations, HIV promotes the development of FOXP3+ Tregs by enhancing monocytic myeloid-derived suppressor cells.79 HIV induces plasmacytoid DC activation via tlr-7 and then promotes plasmacytoid DCs to upregulate the expression of indoleamine 2,3 dioxygenase, thereby facilitating the differentiation of immature CD4+ T cells into Tregs.80 Tregs develop a level of resistance to HIV-induced apoptosis that partly depends on IL-21, which promotes the survival of Tregs and suppresses apoptosis. Accordingly, there is an increased relative number of Tregs in HIV-infected patients.81 CCR5 is an essential co-receptor of HIV. Individuals born with a specific CCR5 mutation are highly resistant to HIV.82,83 Since CCR5 on Tregs is a common receptor for HIV entry, CCR5-targeted therapeutic drugs for the treatment of HIV have also been used to test the treatment of cancer in clinical trials.84,86

Hand-foot-and-mouth disease (HFMD)-associated virus

HFMD, mostly benign with a good prognosis, refers to an infectious disease caused by enterovirus. Common pathogens include Coxsackievirus A16 and enterovirus 71. In cases where the central nervous system is seriously involved, the disease can rapidly progress in a short period, and a wide range of serious complications may occur. The percentages of Th1 and Tc1 cells of the T cell population are significantly higher in mild and severe HFMD patients than those of healthy donors. A similar trend is also identified for the Th17/Treg cell ratio. These findings reveal that the Th1/Th2 and Th17/Treg imbalance exists in HFMD patients, which demonstrates that all these T cells are involved in the pathogenesis of enterovirus 71 infections.87 The Th17 cell proportion and IL-17A and IL-23 levels are remarkably elevated, whereas Treg proportion and IL-10 and TGF-β1 levels are significantly decreased in HFMD patients. IL-37 stimulation increases Tregs and reduces Th17 cells in HFMD patients. Methylprednisolone pulse therapy/methylprednisolone combined with intravenous γ globulin can impact Th17/Treg imbalance by upregulating IL-37 in HFMD.88

Bacterial infections

Listeria monocytogenes

L. monocytogenes is a Gram-positive facultative anaerobic bacterium, and it can pass through the blood circulation to break the blood-brain barrier and infect the central nervous system of the host to cause bacterial meningitis.89L. monocytogenes is highly prevalent in people with immune deficiency, and the mortality rate of listeriosis is as high as 20%–50% in the elderly, pregnant women, and newborn. As previously demonstrated, the expansion of immune-suppressive FOXP3+ Tregs occurs physiologically during pregnancy, and when it is experimentally induced in transgenic mice, it can cause enhanced susceptibility to prenatal pathogens (eg, Listeria and Salmonella species). Reciprocally, susceptibility to infection is uniformly reduced with Treg ablation.90 Live attenuated L. monocytogenes treatment can induce tumor-specific CD8+ T cell responses in mice bearing hepatic metastases. Moreover, the treatment effect can be enhanced by depletion of Tregs by either anti-CD25 or cyclophosphamide treatment.91 Attenuated L. monocytogenes represents a candidate vector for the delivery of cancer vaccines.92 The LmddA-LLO-E7 vaccine, expressing a fusion protein comprising truncated listeriolysin O and human papilloma virus E7 protein, can sufficiently induce a decrease in the proportion of Tregs by preferentially expanding CD4+FOXP3 T cells and CD8+ T cells.93 Because Tregs play an immunosuppressive role, they have different functions in the inflammatory response, which helps to clear the pathogens in the early stage or reduce the damage caused by increased inflammation in the late stage of the disease. Various cytokines and chemokines are involved in the process. Shi et al. found an alternative route of Treg conversion from cytokine-secreting T cells to activated Tregs (aTregs), which was induced by several myeloid-specific chemokines, either via CXC chemokine receptors, or by myeloid cells in a cell-cell contact manner instead of a classic conversion pathway from resting Tregs (rTregs) to aTregs. This provides a possible explanation for the different functions of the Tregs at different stages.94 Dolina et al. found that in low doses of Listeria infections, CD4+ T cells function as classical helpers for the CD8+ T cell responses, whereas infections with higher doses of the same pathogen cause more rapid accumulation of Tregs to suppress CD8+ T cell responses.95

Mycobacterium tuberculosis

M. tuberculosis is a facultative intracellular bacterium with macrophages as host cells. M. tuberculosis is capable of affecting all tissues and organs, most commonly causing lung infections. CD4+CD25+FOXP3+ T cells increase in the blood of tuberculosis patients.96,97 In the initial inflammatory response of tuberculosis, pathogen-specific Tregs are expanded in lymph nodes, whereas these cells are actively culled later through IL-12-induced intrinsic expression of the Th1-cell-promoting transcription factor T-bet.98 IL-4, the archetypal Th2 cytokine, reduces mycobacterial containment in infected macrophages in a dose-dependent manner. IL-4 mRNA shows an association with the increase of Tregs and the decrease of Th1 cytokine levels. Furthermore, IL-4 can subvert mycobacterial containment in human macrophages, probably causing perturbations in Treg-and Th1-linked pathways.99 Most works carried out on animal models describe an increase in Treg levels as M. tuberculosis infections progress. Results from the cynomolgus macaques M. tuberculosis infection model of Angela et al. suggest that elevated Treg levels are a response to inflammation, rather than the cause of tuberculosis progression.100 Luo et al. found that not only Treg percentages but also Th17 cell percentages were higher in patients with active tuberculosis, which reflects the importance of the balance between pro- and anti-inflammatory responses.101

Helicobacter pylori

H. pylori is a chronic infectious pathogen with a high infection rate worldwide. Persistent colonization with H. pylori causes gastritis and predisposes infected individuals to gastric cancer. Epinecidin-1 antimicrobial suppresses IL-10 and then affects FOXP3 expression levels and reduces pro-inflammatory cytokine production. Epinecidin-1 treatment is capable of reducing CD4+FOXP3+ Tregs and Th17 subset populations and clearing persistent H. pylori colonization in mouse models.102 In H. pylori-infected patients, CCR6 (CCL20 receptor) and CXCR1 and CXCR2 (IL-8 and CXCL1-3 receptors) are expressed by a higher proportion of peripheral blood Tregs. H. pylori induces CCL20 production by gastric epithelial cells via cag pathogenicity island-dependent NF-κB signaling. FOXP3+, instead of FOXP3, CD4+ cells from infected mice migrate towards recombinant CCL20 in vitro. Besides increasing Treg numbers, H. pylori infections induce a change in their characteristics.103 H. pylori induces a Treg response, which may facilitate its coexistence with the human host, and ulcers occur when this regulatory response is inadequate.104 Although the infected individuals generate a robust immune response, the pathogen cannot be eradicated in most cases.105 The mechanisms of immune evasion include antigenic variation, regulation of gastric epithelial cell adhesion, evasion of pattern recognition, direct inhibition of T cell proliferation and induction of Treg responses.106,107 Compared with those without H. pylori infections, Treg levels in the gastric and duodenal mucosa of patients with H. pylori infections are higher.108 Furthermore, depletion of Tregs in H. pylori-infected mice lead to increased gastric inflammation and reduced bacterial colonization.109

Salmonella

Salmonella spp. are Gram-negative intestinal bacterial pathogens. Salmonella infections cause a variety of diseases (eg, typhoid, paratyphoid, gastroenteritis, and septicemia) in humans and animals. In persistent Salmonella infections, the activation of Teff cells is reduced and FOXP3+ Tregs increase at early stages of infections. In contrast, in late-stage infections, Teff cells are highly activated, with the pathogen burden and FOXP3+ Tregs reduced. Dynamic regulation of Treg suppressive potency determines the course of persistent bacterial infections.110 In the Salmonella enterica serotype Typhimurium-infected mice, an early colonic Th17 response in total CD4+ T cells occurs, followed by a Th1 bias. Tregs selectively suppress Th cells to shape the immune response.111 S. enterica serotype Typhi-specific Tregs from typhoid volunteers exhibit upregulation of activation molecules post-challenge [eg, human leukocyte antigen (HLA)-DR and lymphocyte function-associated antigen-1 (LFA-1)]. Depletion of Tregs results in increased S. Typhi-specific cytokine production by CD8+ T effector memory cells in vitro. The tissue distribution of aTregs indicates that they may play a pivotal role in typhoid fever by suppressing S. Typhi-specific Teff cell responses.112

Ferroptosis

Ferroptosis refers to a form of non-apoptotic cell death; it shows definite iron dependence, and it is related to lipid peroxidation.113 Ferroptosis is involved in the occurrence and development of many diseases (eg, tissue ischemia-reperfusion injury, neurological diseases, and cancer).114 According to the lymphatic system, cells absorb oleic acid and other antioxidants, thereby protecting cells from ferritin during blood transmission.115 According to Wang et al., CD8+ T cells release interferon γ to downregulate the expressions of SLC3A2 and SLC7A11 in tumor cells, which are the two subunits of the glutamate-cystine antiporter system, thereby impairing the uptake of cystine by tumor cells. Thus, tumor cell lipid peroxidation and ferroptosis are promoted.116 In patients with severe COVID-19, major cardiac involvement is a potentially lethal feature. Histopathological examinations reveal that the cardiac tissue is heavily infiltrated with lymphocytes. The myocardial tissues have been examined for markers of ferroptosis, and the results were positive. A similar ferroptosis signature was present in the myocardium of a COVID-19 subject without myocarditis. This highlights that ferroptosis is a detrimental factor in COVID-19 cardiac damage.117Pseudomonas aeruginosa can cause lower respiratory tract infections, and high expression of pLoxA in P. aeruginosa is reported to cause ferroptosis in bronchial epithelial cells.118 Elevated iron levels are associated with an increased risk of tuberculosis in patients. Ferroptosis has been reported to exist in the CD4+ and CD8+ T cells and regulate the immunity in infections. It is increasingly evidenced that ferroptosis is associated with performance of the inflammation (Figure 2).119 Infection is considered as an area to be investigated more deeply from the perspective of ferroptosis. Although there are no reports about ferroptosis in Tregs, it is worth further investigation.

F2
Figure 2:
The function of ferroptosis during infection. It has been reported that Gpx4 deficiency causes ferroptosis in both CD4+ and CD8+ T cells and impairs immunity responses against both viruses and Leishmania.

Conclusion and perspective

Microorganisms are associated with human beings and critically impact human survival and reproduction as well as the maintenance of immune homeostasis. Persistent infections facilitate the initiation and maintenance of the body's immune system, as well as regulating the host's self-regulation and control of adverse immune reactions, as an attempt to minimize or limit the host's immunopathological damage attributed to infections. Immune regulation of the body is of high importance for maintaining relative stability of the internal environment of the body, which should induce effective immune responses and eliminate pathogenic microorganisms that are invading the body. On one hand, FOXP3+ Tregs can suppress tissue damage attributed to excessive immune responses, which protects the host in most chronic infections. On the other hand, pathogen infections induce FOXP3+ Tregs to suppress the immune response against these pathogens. It is challenging to gain insights into the details of how FOXP3+ Tregs regulate the antiinfection immunity, whereas this will help treat various acute or chronic infectious diseases.

High levels of immune responses will cause autoimmune damage, and low levels of immune responses will facilitate persistent infection of pathogens. Accordingly, how to maintain an appropriate level of immune response during infections has always been one of the research hotspots. Over the past few years, studies have reported that two subsets of CD4+ T cells (ie, Tregs and Th17 cells) play a key role in suppressing excessive immune responses and facilitating immune inflammatory responses. Tregs are a subset of T cells with immunosuppressive effects, which are involved in the regulation of immune response/tolerance and critically help reduce autoimmunity and transplant rejection. Th17 is a relatively new Th subgroup that is inconsistent with conventional Th1 and Th2 cells. It mainly plays a role in promoting immune inflammation by secreting IL-17. Tregs and Th17 cells may regulate the immune response via different mechanisms to maintain a balance and stability of body functions, which plays an important role in the maintenance of immune homeostasis.

As technology is leaping forward, insights are being gained into the immune system and infections. In the early days of treatments, the use of hormones in infectious diseases was significantly effective in controlling the disease, but with many side effects. To address external infections, immune cells release large amounts of inflammatory cytokines, which can result in inflammatory storms due to cascading amplifications. In extensive studies, small-molecule drugs and monoclonal drugs against cytokines have been promoted to treat infections. The desired therapeutic effect has been achieved, and the side effects of broad-spectrum hormones on the body have declined. Moreover, given the different functions of Tregs in different stages of the disease, the treatment of diseases should be explored in depth. In early stages of infections, damaged Tregs can be enhanced or repaired to control inflammation and reduce tissue damage. At stages of chronic infections, it is more suitable to perform targeted therapy to suppress the activity of Tregs and enhance the immune response against pathogens.

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Keywords:

FOXP3; infection; inflammatory disease; regulatory T cells

Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.