T Cell Receptor Is Required for Differentiation, but Not Maintenance, of Intestinal CD4 + Intraepithelial Lymphocytes

Immunity. 2020 Nov 17;53(5):1001-1014.e20. doi: 10.1016/j.immuni.2020.09.003. Epub 2020 Oct 5.


The gut epithelium is populated by intraepithelial lymphocytes (IELs), a heterogeneous T cell population with cytotoxic and regulatory properties, which can be acquired at the epithelial layer. However, the role of T cell receptor (TCR) in this process remains unclear. Single-cell transcriptomic analyses revealed distinct clonal expansions between cell states, with CD4+CD8αα+ IELs being one of the least diverse populations. Conditional deletion of TCR on differentiating CD4+ T cells or of major histocompatibility complex (MHC) class II on intestinal epithelial cells prevented CD4+CD8αα+ IEL differentiation. However, TCR ablation on differentiated CD4+CD8αα+ IELs or long-term cognate antigen withdraw did not affect their maintenance. TCR re-engagement of antigen-specific CD4+CD8αα+ IELs by Listeria monocytogenes did not alter their state but correlated with reduced bacterial invasion. Thus, local antigen recognition is an essential signal for differentiation of CD4+ T cells at the epithelium, yet differentiated IELs are able to preserve an effector program in the absence of TCR signaling.

Keywords: T cell receptor; TCR repertoire; cell plasticity; intestinal epithelium; intestinal intraepithelial lymphocytes; single-cell gene expression; tissue adaptation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism*
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Clonal Evolution / genetics
  • Clonal Evolution / immunology
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / immunology
  • Immunophenotyping
  • Intestinal Mucosa / immunology*
  • Intestinal Mucosa / metabolism*
  • Intraepithelial Lymphocytes / immunology*
  • Intraepithelial Lymphocytes / metabolism*
  • Mice
  • Receptors, Antigen, T-Cell / metabolism*
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism
  • Signal Transduction
  • Single-Cell Analysis
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism


  • Histocompatibility Antigens Class II
  • Receptors, Antigen, T-Cell
  • Receptors, Antigen, T-Cell, alpha-beta