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

Abstract

The gut epithelium is populated by intraepithelial lymphocytes (IELs), a heterogeneous T cell population with cytotoxic and regulatory properties. Migrating peripheral CD4 + T cells, including regulatory (Treg) and conventional T cells (Tconv), acquire an IEL (CD4-IEL) program upon arrival at the epithelium. However, the specific role of the T cell receptor (TCR) in this process remains unclear. Single-cell TCR repertoire and transcriptomic analysis of intraepithelial CD4 + T cells revealed different extents of clonal expansion and TCR overlap between cell states; fully differentiated CD4-IELs from Tregs or Tconvs were the least diverse. Conditional deletion of TCR on differentiating CD4 + T cells or of MHCII on intestinal epithelial cells prevented CD4-IEL differentiation.However, TCR ablation on developed CD4-IELs did not affect their accumulation.These results indicate that local recognition of a limited set of antigens is an essential signal for the differentiation and adaptation of T cells to the epithelium.

Intestinal cDC1s provide IL-12 dependent and independent functions required for CD4+T cell-mediated resistance toCryptosporidium

“…Because Cryptosporidium is restricted to IECs and does not infect professional APCs, there are basic questions about how parasite-derived antigens gain access to the mLN and whether APCs at the site of infection can acquire parasite antigens and support local CD4 + T cell function (54). Interestingly, IECs can express MHCII, and differentiation of CD4 + T cells into CD4 + CD8αα IELs within the gut requires MHCII expression on IECs (72). During Cryptosporidium infection, IFN-γ signaling on IECs leads to higher MHCII and CIITA expression (32,73 Preprint), which may facilitate the ability of IECs to engage effector CD4 + T cells within the IEL.…”

Non‐zero‐sum microbiome immune system interactions

“…The development of CD4 + CD8αα + IELs is also affected by microbiota members, such as Lactobacillus reuteri [180]. The microbiota-driven expression of MHC-II and programmed deathligand 1 (PD-L1) by IECs is required for the differentiation of CD4 T cells to become CD4 + CD8αα + IELs [181,182].…”