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.

Fig. 1. Multiple pathways for the development of intestinal IEL lineages

Conventional αβ T cell receptor (TCRαβ)⁺CD8αβ⁺ intraepithelial lymphocytes (IELs) originate from naive CD8⁺ T cells that are primed by foreign antigens in the gut-associated lymphoid tissue (GALT) to divide, acquire a cytolytic effector programme and upregulate expression of α4β7 integrin and CC-chemokine receptor 9 (CCR9). They traffic through the lymph to reach the blood circulation and home to the gut epithelium, where on exposure to transforming growth factor-β (TGFβ), they acquire expression of αEβ7 integrin. By contrast, unconventional TCRαβ⁺ IELs acquire their effector programme and the expression of gut-homing receptors in the thymus through agonist stimulation by self antigens before reaching the gut epithelium. Unconventional TCRγδ⁺ IELs arise in the thymus (and also outside the thymus) as naive lymphocytes that already express α4β7 integrin and CCR9. They divide and acquire their effector programme in the GALT after exposure to butyrophilin-like protein (BTNL) ligands expressed by intestinal epithelial cells and then recirculate through Peyer’s patches and the lymph back to the blood and intestinal epithelium. Note that unconventional TCRαβ⁺ and TCRγδ⁺ IELs respond to self ligands rather than foreign ligands. Group 1 innate lymphoid cells (ILC1s) originate as fully differentiated effector cells from a dedicated ILC progenitor found in fetal liver and in adult bone marrow. The developmental pathway of CD4⁺CD8αα⁺ IELs is not shown here but was recently reviewed. AHR, aryl hydrocarbon receptor; DN, double negative; DP, double positive; IL-15Rβ, IL-15 receptor-β; NKR, natural killer receptor; PD1, programmed cell death protein 1; T-bet, T cell-specific T box transcription factor T-bet; TCRV, TCR variable chain.

Fig. 2. Stereotypic functions of intestinal IEL lineages

Intestinal intraepithelial lymphocyte (IEL) lineages engage in multiple interactions with epithelial cells, dietary components and the microbiota. They have common properties, including expression of type 1 cytokines and cytolytic properties mediated by granzyme B upon exposure to IL-12, IL-18 and IL-15 produced in the local environment. They can directly kill stressed epithelial cells that express ligands for activating natural killer (NK) cell receptors such as NK cell receptor group 2, member D (NKG2D). In addition to these shared properties, individual lineages respond to specific ligands, including butyrophilin-like proteins (BTNLs) for T cell receptor variable γ-chain 7 (TCRVγ7)⁺ IELs and MHC ligands for TCRαβ⁺ IELs. Note that the TCRαβ of unconventional TCRαβ⁺ IELs is cross-reactive, such that it can recognize multiple MHC ligands. AHR, aryl hydrocarbon receptor; HVEM, herpesvirus entry mediator; IL-12R, IL-12 receptor; IL-15R, IL-15 receptor; IL-18R, IL-18 receptor; ILC1, group 1 innate lymphoid cell; T-bet, T cell-specific T box transcription factor T-bet; TL, thymus leukaemia antigen.