Development, ontogeny, and maintenance of TCRαβ+ CD8αα IEL

https://doi.org/10.1016/j.coi.2019.04.010Get rights and content

Highlights

  • Intestinal IEL are a heterogeneous lymphocyte population.

  • In adult animals, the majority of CD8αα IEL precursors are self-reactive thymocytes that undergo agonist selection.

  • Alternative, and likely functionally distinct, precursors exist.

The intestinal epithelium is the outermost cellular layer that separates the body from the gut lumen. The integrity of this protective mucosal barrier is crucial and maintained by specialized cells—intraepithelial lymphocytes (IEL). Much research has been conducted on these cells and our overall understanding of them is increasing rapidly. In this review we focus on the TCRαβ+ subset of CD8αα IEL. We discuss recent studies that shed light on the development, ontogeny, maintenance, and functional characteristics of CD8αα IEL, and highlight yet unanswered questions for future studies.

Introduction

Intestinal intraepithelial lymphocytes (IEL) are comprised of innate lymphoid cells and T cells within the gut epithelium [1, 2, 3]. The T cell IEL include conventional resident memory TCRαβ+ CD4+ and CD8αβ+ T cells, as well as unconventional TCRαβ+CD4CD8αα+β and TCRγδ+ IEL [1,4]. Despite these differences in their origin, IEL bear notable functional and phenotypic commonality, including expression of T-bet, NK receptors of the Ly49 family, IL-15 receptors, and an activated phenotype with high expression of CD69 [1,5]. IEL patrol the epithelium and help to maintain homeostasis and integrity of the barrier surface between gut lumen and the body [1,6,7]. Effector mechanisms include stimulation of antimicrobial peptide production in epithelial cells through HVEM stimulation [8] and epithelial cell proliferation via an AHR regulated pathway [9]. IEL further have a cytolytic profile, including Granzyme B expression [1,4,10]. Within IEL, this review will focus on the TCRαβ+CD4CD8αα+β IEL (hereafter called CD8αα IEL) and emerging concepts about their development.

Section snippets

Intestinal CD8αα IEL

There are two main features that distinguish CD8αα IEL from conventional CD8+ or CD4+ IEL: (1) self-reactive TCRs and (2) a co-receptor that consists solely of CD8αα homodimers. CD8αα homodimers bind the nonclassical MHC class I molecule thymus leukemia antigen (TL), which is expressed by intestinal epithelial cells [11,12]. Some research suggests CD8αα regulates TCR signaling strength, and TL-deficient mice develop more severe disease in experimental models of inflammatory bowel disease (IBD) [

Thymic development of CD8αα IEL precursors

Recent work has shed much light on the developmental pathways of CD8αα IEL. Although there was controversy in the past about the site of CD8αα IEL development [15,27,28], there now is agreement that the majority of these cells arise in the thymus [1,4]. IELp have been identified within the CD4CD8 (DN) TCRαβ+ pool [17,18••,19••,29,30••]. During thymic maturation, IELp, like conventional T cells, upregulate MHC class-I (i.e. H-2Kb in C57BL/6 mice) and also CD122 [18••,19••,31]. CD122 is a

A second thymic precursor for CD8αα IEL

While the PD-1+ self-reactive IELp is a prominent and well-studied precursor, recent reports indicate that an alternative and potentially functionally distinct precursor also exists [17,19••]. Within the TCRαβ+ DN population, IELp were reported to express either PD-1 [18••] or Tbet [30••], yet these two populations are mutually exclusive [19••]. The PD-1+Tbet (Type A) IELp reside in the thymic cortex, and were reduced in both classical and nonclassical MHC class-I knockout models (suggesting

Emigration and tissue seeding of CD8αα IEL

After selection in the thymus, conventional T cell progenitors upregulate the transcription factor KLF2 and the sphingosine-1 phosphate receptor 1 (S1PR1) and migrate along an S1P gradient through thymic perivascular spaces and into the vasculature [31,43, 44, 45]. The same emigration mechanism seems to apply to IELp, as the presence of gut CD8αα IEL was dependent on both KLF2 and S1PR1, even though neither of these molecules were expressed by CD8αα IEL in the gut [46]. Instead, KLF2 and S1PR1

Future questions for the study of CD8αα IEL

In the last decade or so, much effort has been put into better understanding the developmental pathways and functional values of CD8αα IEL. Traditionally, studies of IELp populations heavily rely on adoptive transfer experiments, in which donor populations are injected into congenically distinct T cell deficient (i.e. Rag-10 or Rag-20) hosts. This approach can rightly be criticized as compromised, as only a small number of IELp can be isolated from thymi, and because they need to be transferred

Conflict of interest statement

Nothing declared.

References and recommended reading

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

  • • of special interest

  • •• of outstanding interest

Acknowledgement

KAH received funding from the National Institutes of Health (R37 AI39560).

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    Current address: Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia.

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