Review
Intestinal T cells: Facing the mucosal immune dilemma with synergy and diversity

https://doi.org/10.1016/j.smim.2009.03.003Get rights and content

Abstract

The epithelium of the gastrointestinal tract, which represents the greatest body surface area exposed to the outside environment, is confronted with a plethora of foreign and potentially harmful antigens. Consequently, the immune system of the gut faces the daunting task of distinguishing harmless dietary proteins and commensal bacteria from potentially dangerous pathogens, and of then responding accordingly. Mucosal T cells play a central role in maintaining barrier function and controlling the delicate balance between immune activation and immune tolerance. This review will focus on the unique features of mucosal T cell subsets that reside in the epithelium and lamina propria of the gut.

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.

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