Origin, trafficking, and intraepithelial fate of gut-tropic T cells

J Exp Med. 2013 Aug 26;210(9):1839-54. doi: 10.1084/jem.20122588. Epub 2013 Aug 5.

Abstract

The small intestine epithelium (SI-Ep) harbors millions of unconventional (γδ and CD4(-) CD8(-) NK1.1(-) TCRαβ) and conventional (CD8αβ and CD4) T cells, designated intraepithelial lymphocytes (IELs). Here, we identified the circulating pool of SI-Ep-tropic T cells and studied their capacity to colonize the SI-Ep under steady-state conditions in SPF mice. Developmentally regulated levels of α4β7 endowed recent thymic emigrants (RTEs) of unconventional types with higher SI-Ep tropism than their conventional homologues. SI-Ep-tropic RTEs, which in all lineages emerged naive, homed to the SI-Ep, but this environment was inadequate to stimulate them to cycle. In contrast, conventional and, unexpectedly, unconventional T cells, particularly Vγ7(+) (hallmark of γδ IELs), previously stimulated to cycle in the gut-associated lymphoid tissue (GALT), proliferated in the SI-Ep. Cycling unconventional SI-Ep immigrants divided far more efficiently than their conventional homologues, thereby becoming predominant. This difference impacted on acquisition of high Granzyme B content, which required extensive proliferation. In conclusion, SI-Ep-tropic T cells follow a thymus-SI-Ep or a GALT-SI-Ep pathway, the latter generating highly competitive immigrants that are the sole precursors of cytotoxic IELs. These events occur continuously as part of the normal IEL dynamics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Division
  • Cell Lineage / immunology*
  • Cell Movement / immunology*
  • Cell Proliferation
  • Epithelial Cells / cytology
  • Epithelial Cells / immunology
  • Epithelium / immunology*
  • Granzymes / metabolism
  • Integrins / metabolism
  • Intestine, Small / cytology*
  • Lymphoid Tissue / cytology
  • Mice
  • Mice, Inbred C57BL
  • Phenotype
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism
  • Receptors, CCR / metabolism
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / immunology*
  • Thoracic Duct / cytology
  • Thymocytes / cytology
  • Thymocytes / metabolism
  • Thymus Gland / cytology
  • Thymus Gland / growth & development

Substances

  • CC chemokine receptor 9
  • Integrins
  • Receptors, Antigen, T-Cell, alpha-beta
  • Receptors, Antigen, T-Cell, gamma-delta
  • Receptors, CCR
  • integrin alpha4beta7
  • Granzymes