Diverse developmental pathways of intestinal intraepithelial lymphocytes

Abstract

The intestinal epithelial barrier is patrolled by resident intraepithelial lymphocytes (IELs) that are involved in host defence against pathogens, wound repair and homeostatic interactions with the epithelium, microbiota and nutrients. Intestinal IELs are one of the largest populations of lymphocytes in the body and comprise several distinct subsets, the identity and lineage relationships of which have long remained elusive. Here, we review advances in unravelling the complexity of intestinal IEL populations, which comprise conventional αβ T cell receptor (TCRαβ)+ subsets, unconventional TCRαβ+ and TCRγδ+ subsets, group 1 innate lymphoid cells (ILC1s) and ILC1-like cells. Although these intestinal IEL lineages have partially overlapping effector programmes and recognition properties, they have strikingly different developmental pathways. We suggest that evolutionary pressure has driven the recurrent generation of cytolytic effector lymphocytes to protect the intestinal epithelial layer, but they may also precipitate intestinal inflammatory disorders, such as coeliac disease.

Resident memory CD8 T cells persist for years in human small intestine

“…Most mice are maintained in specific pathogen-free (SPF) conditions that reduce their microbiome diversity, which in turn influence the immune homeostasis and response to pathogens in the intestine (Maynard et al, 2012;Tao and Reese, 2017). Moreover, murine intraepithelial (IE) CD8 T cells constitute a heterogeneous population of unconventional CD8αα+ and conventional CD8αβ+ T cells, with partially overlapping effector properties but different developmental origins (McDonald et al, 2018). In contrast, their human counterparts mainly consist of conventional CD8αβ-expressing cells (Jabri and Ebert, 2007).…”

T cell receptor is required for differentiation but not maintenance of intestinal intraepithelial lymphocytes

“…Finally, we identified three non-Treg clusters, one of them composed mostly of Tomato + cells (cluster 0), indicating Treg origin, while the other two (clusters 2 and 4) contained a mix of Tomato + and Tomatocells (Figure 2A, Figure S2C, F, Table S1). Cluster 2 was rather homogeneous containing CD8a-expressing cells with a "full IEL program" (Cheroutre et al, 2011;McDonald et al, 2018), which included the expression of Gzma, Gzmb,Cd244 (2B4),and Itgae (CD103) (Figure 2A, Figure S2C, Table S1). Trajectory analysis allowed the inference of a peripheral CD4 + T cell differentiation hierarchy as they gain access to the epithelium ( Figure 2B).…”

“…The transition to an IEL program includes upregulation of NK-and cytolytic-molecules as well as CD8aa (Cheroutre et al, 2011;McDonald et al, 2018), with concomitant downregulation of TCR signaling. To evaluate the role of the TCR signaling in establishing the IEL program, and in the maintenance of differentiated IELs, we crossed…”

“…In addition to these features, tissue imprinting influences T cell subset differentiation and function (Faria et al, 2017). In the intestine, T cells located in the lamina propria (LP), and in the intraepithelial (IE) compartment display gut-specific characteristics, such as expression of gut-homing integrins, but differ markedly in TCR usage, migration patterns and function (McDonald et al, 2018).…”

“…Intestinal intraepithelial lymphocytes (IELs) comprise a heterogeneous population of T cells, yet they all share common features such as tissue residency, cytotoxic potential, activated phenotype, and expression of CD8aa homodimers (Cheroutre et al, 2011;McDonald et al, 2018). Previous studies propose that CD8aa homodimers, in contrast to conventional CD8ab heterodimers, work as TCR co-repressors by binding to thymus leukemia (TL) antigen expressed on epithelial cells, resulting in decreased antigen sensitivity of the TCR (Cheroutre and Lambolez, 2008).…”