ReviewIntestinal T cells: Facing the mucosal immune dilemma with synergy and diversity
Introduction
The intestine represents a major immune organ with several specialized lymphoid structures and cell types and has been roughly divided into the inductive organized gut-associated lymphoid tissue (GALT) and effector sites. Organized GALT includes Peyer's Patches (PP), isolated lymphoid follicles, the appendix, and the gut draining mesenteric lymph nodes (MLN), whereas effector cells accumulate in the lamina propria (LP) as lamina propria lymphocytes (LPL) and within the epithelium as intraepithelial lymphocytes (IEL).
The challenging function of the gut immune system is to prevent penetration and spreading of commensals and pathogens while avoiding excessive or unnecessary immune responses. Several levels of protective barriers can be distinguished that act to avert microbial invasion of the host. The first line of passive defense attempts to prevent intact antigens and pathogens from entering the body and encountering the immune system (immune exclusion). The second immune barrier is formed by an active innate immune sensing system that provides a combination of maintaining homeostasis and initiating active pro-inflammatory immune responses to microbial invasion by immune surveillance at the mucosal surface. Finally, a highly developed adaptive immune system regulates the responses to antigens that have crossed the epithelial barrier.
The mucosal epithelium is formed by a single layer of tightly connected intestinal epithelial cells (IEC) and acts as a physical protective wall, separating luminal antigens from the underlying tissue compartments. The microvilli of the brush border and the tight junctions between the IEC are essential structural components in regulating permeability of the mucosal border. Specialized IEC, such as the paneth cells and associated innate immune cells also secrete several defensive compounds including mucins, proteolytic enzymes, nitric oxide, and anti-microbial peptides, both constitutively and in response to microbes [1]. In addition to these physical defense systems, antibody-secreting B cells play a key role in maintaining immunological quiescence (reviewed in Ref. [2]). At least 70% of all plasma cells are found in the gut LP and there is more IgA secreted than the total of all other Ig isotypes combined [3]. IgA class-switching is promoted by TGF-β, a cytokine that is abundantly present in the gut mucosa and the secretion of IgA is controlled by several factors including IL-6 and retinoic acid [4]. Most plasma cells produce dimers of secretory IgA (sIgA) antibodies that are exported to the gut lumen and function by entrapping dietary antigens and micro-organisms in the mucus leading to their excretion and by preventing microbial components from attaching to the epithelium. In the gut wall, locally produced IgA can also interact with antigens that have reached the LP and the resulting immune complexes are either taken up by phagocytosis or transcytosed back to the lumen, again enforcing immune exclusion [5].
The barrier is not absolute however and under normal conditions there is extensive crosstalk between the luminal microbes and all arms of the mucosal immune system, coordinated by the IEC and dendritic cells (DC) as messengers. The importance of these interactions is mirrored by the fact that without bacterial colonization of the intestine the structure and function of the intestine itself, including the mucosal immune system, are highly impaired. The crosstalk between the outside environment and concealed immune system is executed via continuous sampling of luminal antigens. The so-called M cells, which are specialized enterocytes that are located in the follicle-associated epithelium, constantly transport intact antigens to the mucosal lymphoid tissue underneath for processing and antigen presentation [6]. Their primary function of trans-cellular endocytosis is facilitated by several distinctive morphological features including a reduced brush border, the absence of a thick glycocalyx, and lack of enzymatic activity. Inevitably perhaps, M cells are also used by many pathogens as a route of entry into the body [6]. Besides these “gateways to the mucosal immune system”, DC have been shown to take up apoptotic IEC and their contents (such as endocytosed antigens) in addition to direct sampling of luminal antigens across the mucosal epithelia without compromising the integrity of the barrier. These processes are mainly associated with promoting tolerance and immune suppression in order to prevent damage of the intestinal barrier and for maintenance of immune homeostasis. In addition, the controlled sampling may also allow for the generation of immune memory before invasion by the pathogen. Overall, the sampling of the gut content may be a mechanism to specifically “adapt” the mucosal immune system to the environment (and therefore also the pathogens likely to be encountered) by the individual.
In the event however that pathogens cross the barrier and gain uncontrolled access to the mucosal immune system, strong and protective immune responses may be initiated that eliminate infections before they become apparent or spread systemically. The rapid and effective protection is ensured by the presence of numerous DC, macrophages, and plasma cells as well as various subsets of effector T cells. Both the LP and the epithelial compartment contain large numbers of antigen-experienced T cells that play a crucial role in protection of the barrier and the host. These memory T cell subsets differ significantly from each other in their ontogeny, the type of antigens they recognize, the signals they received for their differentiation, and the specific effector and/or regulatory function they exert. In this review we will focus on the diverse subsets of mucosal T cells. We will address issues regarding their development, differentiation, function, and interaction with other cell types in the intestinal mucosa.
Section snippets
Mucosal T cell subsets
In the intestine, large populations of T cells reside in three main compartments; the organized GALT, the LP, and the epithelium. Whereas organized structures of the GALT, such as the MLN, contain naïve T cells, almost all T cells in the LP and epithelium display characteristics of an effector/memory phenotype. Although these frontline T cells are notoriously heterogeneous with regard to their phenotype and function, two major subsets can be distinguished based on T cell receptor (TCR) and
IEL and LPL
Intraepithelial lymphocytes reside within the columnar epithelial layer. When they have been looked for, they have been found in all vertebrates that possess a thymus, in both small and large intestine. However, their frequencies vary along the gut and from species to species. In the mouse, it is estimated that there is approximately one IEL per 5–10 IEC in the small intestine versus one IEL per 40 IEC in the colon [8]. In the small intestine of mice a large population of IEL expresses TCRγδ,
Type a mucosal T cells
Type a mucosal T cells are progeny of conventional naïve T cells and they have much in common with the antigen-induced memory cells in the periphery although they also display some distinct features. Type a cells gradually increase with age when more and more antigen-experienced T cells migrate and accumulate in the gut mucosa as long-lived memory cells. In contrast to type b mucosal T cells, type a cells are not confined to the epithelial compartment and they are abundant in the LP and the
Type a IEL function and regulation
In the small intestine type a IEL are mostly CD8αβ+TCRαβ+ memory cells that show cytolytic effector function upon antigen challenge. Compared to central memory T cells in the spleen, these effector memory T cells can be rapidly activated and they may provide initial immediate cytotoxic responses to local infection [23] (Fig. 2). Their TCR repertoire is more restricted than that of peripheral memory CD8αβ+ T cells suggesting that repeated re-stimulation in the intestine may lead to TCR focusing
Type a LPL function and regulation
All classical CD4+ Th subsets can be found in the intestinal LP including the Th1 subset that drives cell-mediated immune responses associated with intracellular infection and cytotoxicity and the Th2 subset that is involved in IgE production, clearance of helminth infection, and allergic sensitization. However, in the past few years it has become apparent that the LP is also home to (1) a Th cell population that constantly produces pro-inflammatory cytokines such as IL-17A, IL-22, and IL-17F,
Type b mucosal T cells
Most type b mucosal T cells reside in the epithelial compartment of the small intestine and express either TCRαβ or TCRγδ. Although these type b TCRγδ+ and TCR αβ+ IEL are clearly different from one another, they share many “unconventional” characteristics that distinguish them from type a IEL [51]. Type b IEL contain a large number of “self”-reactive T cells and in addition to their activated phenotype they also typically express CD8αα homodimers in the absence of the TCR co-receptors CD4 or
Type b IEL function and regulation
The unique localization of IEL is associated with an unusual T cell repertoire and antigen-specificity. The TCRαβ repertoire of type b is oligoclonal [66], [67] and contains numerous self-reactive TCR [61]. Results showing that the TCR repertoire of TCRαβ+CD8αα+ IEL from the fetal intestine or from littermates in the same cage or from germ-free mice showed the same degree of random oligoclonality suggest that the microflora is not responsible for the antigen specificity of the repertoire of
Concluding remarks
The immune system of the gut constantly faces a delicate balancing act between fighting pathogenic intruders on the one hand, and preventing excessive immune responses to harmless antigens and commensals on the other hand. This dilemma seems to be reflected in the functionally diverse mucosal T cell pallet. At the frontline of the intestinal barrier, cytotoxic effector memory cells and pro-inflammatory Th subsets provide rapid protective immunity, whereas Treg and unique self-reactive IEL
Acknowledgements
This work was supported by a Ter Meulen Fonds fellowship from the Royal Netherlands Academy of Arts and Sciences (FW) and by Grant RO1AI050265 from the National Institute of Allergy and Infectious Diseases. The content is solely the responsibility of the authors and does not necessarily represent the official views of National Institute of Allergy and Infectious Diseases or the National Institutes of Health. This is manuscript 1103 from the La Jolla Institute for Allergy and Immunology.
References (92)
- et al.
The biology of intestinal immunoglobulin A responses
Immunity
(2008) - et al.
The immune geography of IgA induction and function
Mucosal Immunol
(2008) - et al.
IgA and the IgA Fc receptor
Trends Immunol
(2001) - et al.
Retinoic acid imprints gut-homing specificity on T cells
Immunity
(2004) - et al.
Doubting the TCR coreceptor function of CD8alphaalpha
Immunity
(2008) - et al.
Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15
Immunity
(1998) - et al.
Natural regulatory T cells: mechanisms of suppression
Trends Mol Med
(2007) - et al.
TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells
Immunity
(2006) - et al.
Commensal DNA limits regulatory T cell conversion and is a natural adjuvant of intestinal immune responses
Immunity
(2008) - et al.
Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine
Cell Host Microbe
(2008)
The thymus chapter in the life of gut-specific intra epithelial lymphocytes
Curr Opin Immunol
Precursors of functional MHC class I- or class II-restricted CD8alphaalpha(+) T cells are positively selected in the thymus by agonist self-peptides
Immunity
The CD8 isoform CD8alphaalpha is not a functional homologue of the TCR co-receptor CD8alphabeta
Curr Opin Immunol
Thymic selection determines gammadelta T cell effector fate: antigen-naive cells make interleukin-17 and antigen-experienced cells make interferon gamma
Immunity
Biological insights into TCRgammadelta+ and TCRalphabeta+ intraepithelial lymphocytes provided by serial analysis of gene expression (SAGE)
Immunity
Intraepithelial gammadelta+ lymphocytes maintain the integrity of intestinal epithelial tight junctions in response to infection
Gastroenterology
Gammadelta T cells: an important source of IL-17
Curr Opin Immunol
Innate defenses of the intestinal epithelial barrier
Cell Mol Life Sci
Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells
Science
M-cells: origin, morphology and role in mucosal immunity and microbial pathogenesis
FEMS Immunol Med Microbiol
Intraepithelial lymphocytes: exploring the third way in immunology
Nat Immunol
Differences in intraepithelial lymphocyte T cell subsets isolated from murine small versus large intestine
J Immunol
Gamma/delta T cells and the diagnosis of coeliac disease
Clin Exp Immunol
Roles of CD1d-restricted NKT cells in the intestine
Inflamm Bowel Dis
Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1
Nature
Identical T cell clones are located within the mouse gut epithelium and lamina propia and circulate in the thoracic duct lymph
J Exp Med
Generation of gut-homing T cells and their localization to the small intestinal mucosa
Immunol Rev
Rapid acquisition of tissue-specific homing phenotypes by CD4(+) T cells activated in cutaneous or mucosal lymphoid tissues
J Exp Med
Stromal mesenteric lymph node cells are essential for the generation of gut-homing T cells in vivo
J Exp Med
Cutting edge: instructive role of peripheral tissue cells in the imprinting of T cell homing receptor patterns
J Immunol
TGF-{beta}-dependent CD103 expression by CD8(+) T cells promotes selective destruction of the host intestinal epithelium during graft-versus-host disease
J Exp Med
Runx3 regulates integrin alpha E/CD103 and CD4 expression during development of CD4-/CD8+ T cells
J Immunol
CCL25/CCR9 promotes the induction and function of CD103 on intestinal intraepithelial lymphocytes
Eur J Immunol
Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells
Nature
Impaired intestinal localization of mesenteric lymphoblasts associated with vitamin A deficiency and protein-calorie malnutrition
Immunology
Direct analysis of the dynamics of the intestinal mucosa CD8 T cell response to systemic virus infection
J Immunol
Mucosal effector memory T cells: the other side of the coin
Cell Mol Life Sci
Intestinal intraepithelial lymphocytes exert potent protective cytotoxic activity during an acute virus infection
J Immunol
Immunization with baculovirus-expressed recombinant rotavirus proteins VP1, VP4, VP6, and VP7 induces CD8+ T lymphocytes that mediate clearance of chronic rotavirus infection in SCID mice
J Virol
Gut-derived intraepithelial lymphocytes induce long term immunity against Toxoplasma gondii
J Immunol
Direct and antibody dependent cell mediated cytotoxicity against Giardia lamblia by splenic and intestinal lymphoid cells in mice
Gut
Cutting edge: gut microenvironment promotes differentiation of a unique memory CD8 T cell population
J Immunol
CD8alphaalpha-mediated survival and differentiation of CD8 memory T cell precursors
Science
Expression of the thymus leukemia antigen in mouse intestinal epithelium
Proc Natl Acad Sci USA
T cell responses modulated through interaction between CD8alphaalpha and the nonclassical MHC class I molecule, TL
Science
High sensitivity of intestinal CD8+ T cells to nucleotides indicates P2X7 as a regulator for intestinal T cell responses
J Immunol
Cited by (74)
Cellular and molecular bases of refractory celiac disease
2021, International Review of Cell and Molecular BiologyGastrointestinal Mucosal Immunology and Mechanisms of Inflammation
2020, Pediatric Gastrointestinal and Liver Disease, Sixth EditionComparison of inflammatory cytokines in peritoneal fluid at source control surgery for abdominal sepsis
2017, American Journal of SurgeryCitation Excerpt :Significant elevations of peritoneal IL-6, IL-17, IL-5, and HGF in the VAC group at primary SCL highlight interesting cytokine functions and relationships that may enhance our understanding of abdominal sepsis pathophysiology on a molecular level. IL-6, and other cytokines are able to activate Th17 T cells, a subset of T cells located within the intestinal tract, which function to maintain mucosal integrity, protect from invading organisms and maintain gut homeostasis.25 Some optimal level of IL-17 expression is required to fight infection, however excessive production of IL-17 and neutrophil recruitment likely produces a hostile pro-inflammatory environment.
DN TCRαβ Intraepithelial T Cell Development in the Thymus
2016, Encyclopedia of ImmunobiologyIrinotecan (CPT-11)-induced elevation of bile acids potentiates suppression of IL-10 expression
2016, Toxicology and Applied PharmacologyVitamin D and colorectal cancer: Molecular, epidemiological and clinical evidence
2016, British Journal of Nutrition