Review
Gut intraepithelial lymphocyte development

https://doi.org/10.1016/S0952-7915(02)00330-8Get rights and content

Abstract

CD8αβ+ and CD4+ intraepithelial lymphocytes, the progeny of double-positive thymocytes, are oligoclonal T-cell populations that have accumulated in the gut wall as the result of repeated antigenic stimulations, which lead to rounds of traffic through the lymph/blood circuit ending in an α4β7-integrin-driven homing all along the gut mucosa. In contrast, CD8αα+ intraepithelial lymphocytes, which may be TCRγδ+ or αβ+, result in part from local differentiation in the gut, but studies comparing euthymic and athymic mice suggest a thymic double-negative origin for many of them.

Introduction

Intraepithelial lymphocytes (IEL) consist mostly of Tlymphocytes belonging to two main categories. In normal adult mice, approximately half express an αβTCR and CD4 or CD8αβ coreceptors. Like most peripheral Tcells, these cells are the progeny of thymocytes originating from the main ‘double-positive (DP) thymic pathway’ of T-cell differentiation, and thus are usually described as thymus-dependent IEL; they are extremely rare in young nude mice but can be detected as these mice age. The remaining IEL express CD8αα homodimers, a phenotype found almost exclusively in the gut mucosa. Since CD8αα IEL are found in nude mice and in neonatally thymectomized mice, they are commonly described as ‘thymus-independent IEL’. They consist of TCRγδ+ or αβ+ cells in about equal proportions in adult normal mice; in nude mice, however, CD8αα+ TCRαβ+ IEL are markedly reduced.

In this brief review, we discuss recent perspectives on two aspects of IEL: TCR repertoire formation among TCRαβ+CD8αβ+ and CD8αα+ IEL in the small bowel; and the possible ontogeny of CD8αα+ IEL.

Section snippets

From DP thymocytes to CD4+ or CD8αβ+ IEL: the ‘shaping up’ of distinct, oligoclonal TCR repertoires throughout the small bowel

Almost 25 years ago 1., 2., transfer experiments of labeled lymphocytes established particular homing patterns of cells derived from different lymphoid organs. Small Tlymphocytes located in the peripheral lymphoid organs and circulating in the thoracic duct (TD) were found to home equally well to all lymphoid organs, including the Peyer's patches (PP). In contrast, T blasts recovered from the mesenteric lymph nodes (MLN) or from the TD (which drains the MLN) homed selectively to the gut wall,

The importance of cell activation and integrin expression

Studies by Lefrançois et al. 3., 4•., 5•. have demonstrated that the activation state and expression of certain integrin complexes guide T-cell homing to the gut. These authors used a transgenic (tg) mouse model expressing a TCR specific for an ovalbumin peptide presented on MHC class I molecules; antigen-specific T cells were identified using tetrameric MHC–peptide complexes. Naive tg TCR+ cells were not found in the gut wall, and accumulated as IEL and LPL only after specific immunization;

The source of antigen and the role of cell migration

The first T-cell activation by enteric antigens probably occurs mainly in the GALT, including the PP. These small lymphoid structures are scattered along the gut mucosa and are covered by unique epithelial cells (M cells) specialized in the transport of various antigenic pathogens from the gut lumen into the mucosa (reviewed in [6]). Immature antigen-presenting dendritic cells (DC) located in close proximity to M cells have the capacity to migrate into the interfollicular areas of the PP (T

The role of antigen in repertoire development

Re-exposure to the same gut antigens will then stimulate memory T cells present not only in the GALT but also as IEL and LPL, leading to the progressive accumulation of cells with the corresponding TCR repertoires. With respect to the stimulation of IEL and LPL, it has been observed that DC are also found in the intestinal villi and, when activated, can penetrate the epithelium and send dendrites to the epithelial surface, thus being able to directly sample luminal antigens and to present them

The origin of the CD8αα+ IEL is still uncertain

Although it is clear that the CD8αα+ IEL do not transit through a DP stage in the thymus, their precise ontogeny is still a matter of debate. Although they are derived from bone-marrow stem cells, the intermediate stages of their differentiation, as well as the sites where they develop, remain ill-defined. Two sites have been proposed: the cryptopatches (CP) of the gut wall and, somewhat surprisingly, the thymus itself.

The implication of CP in the ontogeny of CD8αα+ IEL

CP are post-natal lymphoid aggregates situated along the gut mucosa between the crypts and are in immediate contact with the epithelium. They contain small lymphocytes with a c-kit+IL-7-R+CD44+ phenotype, apparently representing an early immature step in the T-cell lineage as suggested by the presence of CD3ε and germline TCRγ and β gene transcripts [16••]. CP lymphocytes do not have a thymic origin, since CP of nude mice are similar to those of euthymic mice in structure, number and cell

The implication of the thymus in the ontogeny CD8αα+ IEL

A contribution of the thymus to the generation or expansion of CD8αα+ IEL is suggested by the quantitative comparison of the populations of IEL in euthymic versus nude mice: in nude mice, TCRγδ+ IEL are 2–5-times less abundant, and TCRαβ+CD8αα++ IEL are even fewer, than in euthymic mice.

Direct evidence for an early thymic origin of at least some TCRγδ+ and CD8αα+TCRαβ+ IEL has been provided by grafting fetal or neonatal thymi into athymic mice: IEL of these phenotypes and bearing a genetic

Conclusions

The development of the ‘thymus derived’ populations of IEL, resulting from the main DP thymic pathway, appears now reasonably clear. In contrast, a detailed understanding of the ontogeny of TCRγδ+ or αβ+ CD8αα+ IEL, which involves novel local lymphoid structures and pathways of T-cell differentiation, selection and migration different from the better-explored DP pathway, requires more study.

Acknowledgements

The authors wish to thank James Di Santo and the members of our unit for their critical reading of the manuscript and helpful discussions. This work was supported by grants from Institut Pasteur, from Institut National de la Santé et de la Recherche Médicale and from Collège de France.

References and recommended reading

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

  • • of special interest

  • •• of outstanding interest

References (29)

  • A. Iwasaki et al.

    Localization of distinct Peyer's patch dendritic cell subsets and their recruitment by chemokines macrophage inflammatory protein (MIP)-3α, MIP-3β and secondary lymphoid organ chemokine

    J Exp Med

    (2000)
  • A. Iwasaki et al.

    Unique functions of CD11b+, CD8α+ and double-negative Peyer's patch dendritic cells

    J Immunol

    (2001)
  • F.P. Huang et al.

    A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes

    J Exp Med

    (2000)
  • D. Masopust et al.

    Preferential localization of effector memory cells in nonlymphoid tissue

    Science

    (2001)
  • Cited by (68)

    • Gut immunity in European sea bass (Dicentrarchus labrax): a review

      2021, Fish and Shellfish Immunology
      Citation Excerpt :

      Sea bass TcRγ chain undergoes spontaneous rearrangement in the GIT [88] due to the expression of RAG. Spectratyping analysis performed on the same animal confirmed differences of thymus and gut V/C combination, suggesting the possibility that the sea bass intestine be a site of T cell somatic rearrangement, as demonstrated in zebrafish [96], carp [97] and mammals [98]. RAG-1 gene transcripts were quantified in sea bass [35]: although intestinal γδ T cell differentiation is not yet known, sea bass RAG-1 expression was positively correlated with CD8-α transcripts in the gut [35].

    • Human intraepithelial lymphocytes

      2018, Mucosal Immunology
    • Mucosal Immunity

      2018, Comprehensive Toxicology: Third Edition
    • Adaptive immune responses at mucosal surfaces of teleost fish

      2014, Fish and Shellfish Immunology
      Citation Excerpt :

      The rag1 expression in the thymus as well as in the intestinal epithelium indicates that the recombination of immune receptors (probably TCR) can occur in both organs [77,93]. As mentioned above, an extra-thymic origin of IELs has been suggested in mammals too [89,94–96]. In addition, decades ago it was shown in mammals that TCRγδ/CD8αα IEL can develop in the absence of a functional thymus [97] and more recently the role of the gut as a primary lymphoid organ has been postulated [98].

    • Memory CD4<sup>+</sup>CCR5<sup>+</sup> T cells are abundantly present in the gut of newborn infants to facilitate mother-to-child transmission of HIV-1

      2012, Blood
      Citation Excerpt :

      More recent studies in neonatal macaques indicated the presence of a CD4+CCR5+ T cells in the lamina propria with subepithelial localization.25 In contrast, the results of the present study showed the abundance of memory CD4+ T cells with a specific Th phenotype in the gut epithelium, which seems to be a unique feature of the human fetal and infant gut mucosa, because epithelial lymphocytes in adults are mostly CD8+ T cells.14,26 As expected from their phenotype (CCR5+CCR6+HLA-DRhigh), these CD4+ T cells in fetal and infant gut mucosa were highly susceptible to infection with HIV-1, in contrast to neonatal blood CD4+ T cells.

    • T cell diversity and TcR repertoires in teleost fish

      2011, Fish and Shellfish Immunology
      Citation Excerpt :

      In mammals, a number of special T cell populations located in particular tissues have been defined. For example, the intra-epithelial αβ T cells present in the gut mucosa are composed of several subsets with specific repertoires and marker signatures (reviewed in [119,120]). Another example of such cells are the mouse skin-resident, TR γδ+ dendritic epidermal T cells (DETCs), which express canonical TR (TRGV5/TRDV1) [121,122].

    View all citing articles on Scopus
    View full text