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Innate-like lymphocytes in intestinal infections

Bennett, Michael S.a; Round, June L.b; Leung, Daniel T.a,b

Current Opinion in Infectious Diseases: October 2015 - Volume 28 - Issue 5 - p 457–463
doi: 10.1097/QCO.0000000000000189
GASTROINTESTINAL INFECTIONS: Edited by A. Clinton White Jr and Gagandeep Kang

Purpose of review The mechanisms of immunity against intestinal pathogens are not well understood. Innate-like lymphocytes are a group of recently discovered cells that do not fit into either side of the historical innate-adaptive classification. They are enriched in the intestinal mucosa and participate in gut homeostasis and defense against infections. We will review recent developments in innate-like T lymphocytes and innate lymphoid cells, specifically as they relate to responses to intestinal infections.

Recent findings Recent studies have uncovered further details into antigen presentation to γδ T cells and mucosal-associated invariant T cells, the role of invariant natural killer T cells and mucosal-associated invariant T cells in intestinal infections, and how innate lymphoid cells maintain gut homeostasis and protection.

Summary Innate-like lymphocytes play a major role in the critical early response to intestinal infections and maintaining gut homeostasis. Further studies of the roles these cells play in the human intestinal mucosa will aid in the development of therapeutics against intestinal infections.

aDepartment of Medicine, Division of Infectious Diseases

bDepartment of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, Utah, USA

Correspondence to Daniel T. Leung, MD, MSc, Division of Infectious Diseases, University of Utah School of Medicine, 30 N 1900 E, SOM Room 4C416B, Salt Lake City, UT 84132, USA. Tel: +1 801 581 8804; e-mail:

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The human intestinal tract is home to over 100 trillion microorganisms, outnumbering the cells in our body by at least 10 to 1, with more than 1000 different species known to inhabit it [1]. The challenge of intestinal immunity is to maintain the equilibrium between the host commensal microbes while providing protection from potentially invasive pathogens. Adaptive immune responses, while powerful at later stages of infection, require significant time for clonal expansion of their low-frequency, antigen-specific precursors before they can exert their effects. Innate and innate-like cells, however, with higher numbers of cells at the time of infection, bear preformed receptors, can respond quickly, and provide protective immunity even in cases when an adaptive immune response has not yet formed due to lack of antigen exposure, as is the case with newborns.

Since the discovery of natural killer (NK) cells over 40 years ago, a number of cell types have been discovered, which, based on ontogenic and functional characteristics, blur the lines distinguishing the historical classifications of innate and adaptive immune responses (Table 1). Within these ‘in-between’ cells lie a number of innate-like lymphocytes that may act to bridge the gap between the two arms. γδ T cells, mucosal-associated invariant T (MAIT) cells, and invariant NK T (iNKT) cells all utilize restricted T-cell receptor (TCR) rearrangements, which recognize conserved microbial elements presented on major histocompatibility complex (MHC)-like molecules as opposed to the peptide–MHC complexes that activate classical αβ T cells. In addition, the recently defined innate lymphoid cells (ILCs), which include NK cells, help to fill the gap among lymphocytes that do not fall into the classical categories of T, B, or myeloid lineage cells. Many of these cells participate in the first line of immune defense and are important mediators that modulate subsequent adaptive responses. In this review, we will focus on recent advances in the field of innate-like T lymphocytes and ILCs, with a particular emphasis towards studies examining their roles in protection against intestinal pathogens.

Table 1

Table 1

Box 1

Box 1

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γδ T cells are a subset of T cells which express a TCR γ chain in combination with a TCR δ chain. In humans, peripheral γδ T cells most frequently utilize the Vγ9 and Vδ2 chains, and represent 1–5% of T cells in healthy adults [2], but can reach up to 50% of T cells in a matter of days following an infection [3]. γδ T cells are enriched in the human intestine, mostly as intraepithelial lymphocytes (IELs). In contrast to αβ T cells, which are MHC-restricted, γδ T cells can recognize antigens in both MHC-dependent and MHC-independent ways.

γδ T cells are activated by both microbial and host-derived compounds. They recognize the microbial compound (E)-4-hydroxyl-3-methyl-but-2-enyl pyrophosphate (HMB-PP)TL [4], an essential metabolite in isoprenoid biosynthesis, generated by the majority of gram-negative bacteria and some gram-positive bacteria. They also recognize host-derived phosphoantigens such as isopentenyl pyrophosphate. Recent study has focused on the mechanism behind phosphoantigen sensing and presentation, and several studies have identified butyrophilins as responsible for presenting HMB-PP [5–9]. Once activated, γδ T cells have a range of functions, such as killing infected or stressed target cells, priming CD4+ and CD8+ T cells, providing B-cell help, inducing dendritic cell maturation, and promoting survival of neutrophils and monocytes [10].

Recent studies have demonstrated the role that γδ T cells play in limiting transepithelial pathogen invasion. Edelblum et al.[11] observed that higher numbers of Salmonella typhimurium are seen in the gut of TCR δ defective mice, and that migration of γδ IELs was critical to their function. This effect may be related to their influence on the intestinal mucus layer, as Kober et al.[12] found that γδ-deficient mice had alterations in goblet cells and crypt length in the small intestine. A later study by the same group showed that γδ-deficient mice displayed an altered O-glycan profile in the small intestine compared to wild-type littermates [13]. Further evidence for the importance of γδ T cells in combating intestinal infections comes from research on necrotizing enterocolitis (NEC) [14▪]. Comparison of NEC ileal resections with non-NEC controls showed that γδ T IELs are reduced in NECs, and associated with decreased RAR-related orphan receptor C – a Th17 transcription factor. The authors postulated that interleukin (IL)-17 produced by γδ T cells plays a role in promoting intestinal barrier production early in life, and provided support for this by demonstrating an increase in severity of experimental gut injury in TCRδ-deficient mice.

There is increasing evidence that γδ T cells may share characteristics of, and possibly influence, the adaptive αβ T-cell response. Sheridan et al.[15] showed that the mucosal γδ T-cell response following oral Listeria monocytogenes was retained long term and underwent extensive expansion upon oral challenge, displaying memory-like characteristics. Furthermore, γδ T cells may also act by their influence on αβ T cells in the gut, as McCarthy et al.[16] showed that Vγ9δ2 T cells display gut homing potential upon microbial activation and populate the human intestinal mucosa. These γδ T cells mediated their effect via tumor necrosis factor (TNF)-α and interferon (IFN)-γ upon antigen exposure, and enhanced inflammation by stimulating production of IFN-γ and T-bet expression in colonic αβ T cells.

Taken together, γδ T cells likely play an important role in maintaining gut homeostasis and immunity to pathogens, though most studies of intestinal γδ T cells are limited to mouse models, and their results must be interpreted with the limited homology between mouse and human γδ T cells in mind.

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Mucosal-associated invariant T cells are a recently identified T-cell subset important in the defense against bacteria at mucosal surfaces. They express an invariant TCR α chain (Vα7.2-Jα33/12/20 in humans, Vα19-Jα33 in mice) and variable but restricted TCR β chains. MAIT cells are primarily found in mucosal tissues, such as the liver, lung, mesenteric lymph nodes, and intestinal epithelium [17]. In human peripheral blood, they constitute approximately 1–10% of total T lymphocytes [18], but are far less frequent in wild-type mice, and essentially nonexistent in germ-free mice. In the human intestine, they are located in both the lamina propria and as part of the IEL compartment [19]. Only recently has the ligand for MAIT cells been identified as belonging to a class of transitory intermediates of the riboflavin synthesis pathway [20▪], which are produced by many bacteria and yeast, but not viruses. These vitamin B metabolites are presented on the surface by the nonpolymorphic MHC class I-related protein (MR1) [21]. In addition to activation of MAIT cells through the TCR, it has recently been shown that MAIT cells can be activated by IL-12 and IL-18 in a TCR-independent manner [22▪]. MAIT cells are capable of releasing IFN-γ, TNF-α, and IL-17 in response to stimulation, and recent studies have demonstrated that they also possess cytotoxic activity [23,24▪], killing infected cells via granzyme b and perforin [24▪].

Several recent studies have examined the adaptive capacity of human MAIT cells, which, despite their invariant Vα chain, features variability in both Jα and Vβ chains usage [25▪]. Gold et al.[26▪▪] found that among MAIT cells, different pathogen-specific responses were characterized by distinct TCR usage, both between and within individuals. MAIT cell clones with distinct TCRs were also found to respond differently to a riboflavin metabolite. Their heterogeneity may allow MAIT cells to fine-tune their response to bacterial metabolite variants in the gut [27▪▪]. Soudais et al.[28▪] observed that in mice, most if not all of the MAIT cell ligands in Escherichia coli are related to the riboflavin biosynthetic pathway and display very limited heterogeneity.

HIV infection can result in longstanding damage to the intestinal epithelial barrier and translocation of microbial products from the gut lumen. Several recent studies have revealed that in HIV infection, peripheral blood MAIT cells are decreased [29,30▪–32▪,33,34], possibly due to activation of MAIT cells by translocated microbial products [35]. Such a reduction in MAIT cells is noted in elite controllers [32▪], and does not recover even after successful ART, though long-term ART leads to restoration of MAIT cells in the colon, but not the peripheral blood [30▪]. The possibility remains that decreases of MAIT cells in peripheral blood may be a consequence of migration of MAIT cells to affected tissue, instead of or in combination with depletion of MAIT cells through activation.

Data on the role of MAIT cells in immune responses against intestinal infections are limited. Our group [36▪] has shown that in Vibrio cholerae infection, circulating MAIT cells are activated, and that in children, but not in adults, the frequency of MAIT cells is decreased for at least 90 days after infection. We also found an association of MAIT cells with increases in lipopolysaccharide-specific class-switched antibody responses. This finding is in agreement with a previous finding that MAIT cells are associated with increased antibody-secreting cell response to Shigella lipopolysaccharide in humans given an experimental Shigella vaccine [23].

Despite their sizable presence in the intestinal mucosa, our knowledge of the mechanisms underlying MAIT cell proliferation and effect is limited by the lack of suitable animal models. MAIT cells have been proposed to be a potential target of mucosal vaccination [37], and further study on such interventions is needed.

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Invariant natural killer T cells are a subset of T cells which are so named because they express cell surface markers associated with NK cells, such as CD161 in humans or NK1.1 in mice [38], but also possess an invariant αβ TCR. They represent approximately 1% of IELs in both humans and mice, and approximately 0.1% of human T cells in peripheral blood [39]. In contrast to classical T cells, iNKT cells recognize lipids and glycolipids presented by CD1d – a nonpolymorphic MHC protein expressed on intestinal epithelial cells [40]. iNKT cells mediate their effector function primarily through rapid cytokine release following activation [39], including both Th1 (IFN-γ and TNF-α), Th2 (IL-1, IL-4, and IL-13), and Th17 (IL-17, IL-22) cytokines [38,41]. They have also been shown to enhance B-cell responses through both cognate and noncognate mechanisms [42].

Although much work on iNKT cells has focused on their role in antitumor and autoimmunity, several studies have identified their importance in modulation of immune responses against viral infections [43]. Most recently, in a neonatal mouse model, Zhu et al.[44▪] demonstrated that enterovirus 71 (EV71) infection led to activation of iNKT cells, through a TLR3-mediated mechanism. They found that iNKT cells are involved in protection against EV71 infection, and that CD1d is essential for this protection. Similarly, in a murine model of oral S. typhimurium infection, Selvanantham et al.[45] found that infected mice had higher frequency of iNKT cells in the lamina propria, and that iNKTs produce IFN-γ, in a process mediated by the cytosolic peptidoglycan receptors Nod1 and Nod2. Much remains to be determined in how this rare cell type may be involved in defense against intestinal pathogens in humans.

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Innate lymphoid cells is a collective term for cells with lymphoid morphology that do not contain rearranged antigen receptors and that lack myeloid-specific phenotypic markers [46]. They do not directly recognize antigens, but instead respond to changes in cytokine expression profiles as a result of infection. Group 1 ILC, which includes classic NK cells and ILC1, are responsive to cytokines such as IL-12 and IL-18 [38], and produce IFN-γ. Group 2 ILC (ILC2) responds to IL-25, IL-33, and thymic stromal lymphopoietin, and produce Th2 cytokines such as IL-4, IL-5, and IL-13 [38]. These cells have been mainly studied in the lung [47▪], though they also participate in intestinal immune responses against helminth infections by production of IL-13 and promotion of type 2 immunity [48▪].

Group 3 ILCs (ILC3) are involved in the development of intestinal lymphoid organs, and reside primarily in the small intestine lamina propria. These cells express RORγt, and respond to IL-23 and IL-1β via production of IL-22 and IL-17 [49]. The production of IL-22 by ILC3s has been shown to mediate protection against bacterial pathogens [50], and ILC3s can directly stimulate CD4+ T cells [51▪] and also interact with B cells to aid in T-cell-independent antibody production [52▪].

There is increasing evidence that ILC3s are critically involved in intestinal homeostasis. Mortha et al.[53▪] showed that ILC3s are the primary source of granulocyte macrophage colony-stimulating factor (GM-CSF) in the gut, and that deficient production of GM-CSF led to reduced T regulatory (Treg) numbers and impaired oral tolerance. ILC-driven GM-CSF production was dependent on the ability of macrophages to sense microbial signals and produce IL-1β. Similarly, Hepworth et al.[54▪▪] showed that loss of RORγt + ILCs was associated with dysregulated adaptive immune responses against commensal bacteria and low-grade systemic inflammation, and found that ILCs act as APCs and limit commensal bacteria-specific CD4+ T-cell responses by inducing cell death via MHC class II-dependent mechanisms [54▪▪]. On the contrary, Korn et al.[55▪] observed that CD4+ T cells were found to regulate the number and function of IL-22-producing ILCs and production of antimicrobial peptides. Additionally, recent studies by Goto et al.[56▪▪] and Pickard et al.[57▪] showed that microbial signals leading to production of IL-22 by ILC3s induce intestinal epithelial cell fucosylation. Through experiments using fucosylation-deficient mice, they also showed that fucosylation contributes to protection against S. typhimurium infection and host tolerance of Citrobacter rodentium. Taken together, ILC3 mediates protection against intestinal pathogens through interactions with both microbes and host epithelium.

Unfortunately, nearly the entire body of knowledge on intestinal ILCs is based on studies in animal models, and studies examining the activity of ILCs in the human intestine are needed.

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The functions of innate-like lymphocytes, long overshadowed by studies on adaptive immunity, have steadily increased in the recent years as appreciation grows for their important roles in gut microbial homeostasis and early responses against intestinal infections. However, much work remains to be done in determining the nature of their interactions with the adaptive immune system, particularly their influence on B cells and humoral immunity. Such work could critically inform the development of interventions targeting these cells, with potential applications in diverse fields such as vaccinology, oncology, and autoimmunity.

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Financial support and sponsorship

D.T.L. is supported in part by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number K08AI100923, and a Burroughs Wellcome Fund-American Society of Tropical Medicine and Hygiene Postdoctoral Fellowship in Tropical Infectious Diseases.

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Conflicts of interest

There are no conflicts of interest.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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Shows that MAIT cell activation requires key genes encoding enzymes that form 5-amino-6-D-ribitylaminouracil (5-A-RU), an early intermediate in bacterial riboflavin synthesis.

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Shows that MAIT cell activation is not limited to recognition of bacterial metabolites by the TCR, potentially broadening the roles of MAIT cells to possibly include viral infections and other inflammatory stimuli.

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Shows the ability of MAIT cells to directly kill bacterially exposed cells in an MR1 and degranulation-dependent manner.

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Defines the Vβ usage for MAIT cells, finding that a small number of clonotypes accounts for the majority of MAIT cells in blood and liver, and that additional Vα7.2 rearrangements utilizing Jα12 and Jα20 exist and are functional for MAIT cells.

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Shows that MAIT cells may display adaptive properties by being able to respond to different pathogens based upon TCR sequence.

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Shows how MAIT TCR heterogeneity can fine-tune MR1 recognition in an antigen-dependent manner, potentially modulating MAIT cell recognition.

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Shows that in Vα19 transgenic mice, most, if not all, MAIT cell ligands are related to the riboflavin biosynthetic pathway and display very limited heterogeneity.

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Shows that upon antiretroviral treatment, MAIT cell levels in the colon, but not the blood, are restored.

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Shows that Vα7.2+ CD161– cells, though increased in HIV infection, do not stain positive with an MR1 tetramer, and thus likely do not represent MAIT cells which have down-regulated CD161 upon activation.

32▪. Eberhard JM, Hartjen P, Kummer S, et al. CD161+ MAIT cells are severely reduced in peripheral blood and lymph nodes of HIV-infected individuals independently of disease progression. PLoS One 2014; 9:e111323.

Shows that the loss of MAIT cells as a result of HIV infections seems to be an early event that is independent of later disease stages, and is partially due to the vulnerability of MAIT cells to stimulation by microbial products and cytokines during HIV infection.

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Shows activation of MAIT cells in response to cholera infection, and that changes in MAIT cell frequency correlated with changes in antibody levels.

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Shows that iNKT cells may play a role in the control of enteric viral infections, especially in newborns when adaptive immunity is not fully developed.

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Shows that ILC2 are stimulated by TL1A via its receptor DR3, and that this may be a therapeutic target for allergic lung disease.

48▪. Oliphant CJ, Hwang YY, Walker JA, et al. MHCII-mediated dialog between group 2 innate lymphoid cells and CD4(+) T cells potentiates type 2 immunity and promotes parasitic helminth expulsion. Immunity 2014; 41:283–295.

Shows that MHC II expression in ILC2 is necessary for interaction with antigen-specific T cells in promoting the expulsion of helminths.

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Shows the ability of ILC3 to process antigen and primer CD4+ T-cell responses via MHC class II.

52▪. Magri G, Miyajima M, Bascones S, et al. Innate lymphoid cells integrate stromal and immunological signals to enhance antibody production by splenic marginal zone B cells. Nat Immunol 2014; 15:354–364.

Shows that ILCs can facilitate innate-like antibody production at the interface between the immune and circulatory systems.

53▪. Mortha A, Chudnovskiy A, Hashimoto D, et al. Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 2014; 343:1249288.

Discusses the role of ILC3 in production of GM-CSF, and how lack of GM-CSF production by ILC3 leads to reduced Treg numbers and impaired oral tolerance.

54▪▪. Hepworth MR, Fung TC, Masur SH, et al. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4+ T cells. Science 2015; 348:1031–1035.

Demonstrates the mechanism by which ILC3 are able to regulate gut homeostasis by directly inducing commensal-specific CD4+ T-cell death in the gut.

55▪. Korn LL, Thomas HL, Hubbeling HG, et al. Conventional CD4+ T cells regulate IL-22-producing intestinal innate lymphoid cells. Mucosal Immunol 2014; 7:1045–1057.

Shows that CD4+ T cells have the capacity to regulate intestinal ILCs and production of antimicrobial peptides.

56▪▪. Goto Y, Obata T, Kunisawa J, et al. Innate lymphoid cells regulate intestinal epithelial cell glycosylation. Science 2014; 345:1254009.

Shows that ILC3 induce fucosylation of epithelial cells in the gut, and that disruption of fucosylation led to increased susceptibility to Salmonella infection.

57▪. Pickard JM, Maurice CF, Kinnebrew MA, et al. Rapid fucosylation of intestinal epithelium sustains host-commensal symbiosis in sickness. Nature 2014; 514:638–641.

gamma delta T cells; innate lymphoid cells; innate-like lymphocytes; invariant natural killer T cells; mucosal-associated invariant T cells

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