CRTAM determines the CD4+ cytotoxic T lymphocyte lineage

J Exp Med. 2016 Jan 11;213(1):123-38. doi: 10.1084/jem.20150519. Epub 2015 Dec 22.

Abstract

Naive T cells differentiate into various effector T cells, including CD4(+) helper T cell subsets and CD8(+) cytotoxic T cells (CTL). Although cytotoxic CD4(+) T cells (CD4 +: CTL) also develop from naive T cells, the mechanism of development is elusive. We found that a small fraction of CD4(+) T cells that express class I-restricted T cell-associated molecule (CRTAM) upon activation possesses the characteristics of both CD4(+) and CD8(+) T cells. CRTAM(+) CD4(+) T cells secrete IFN-γ, express CTL-related genes, such as eomesodermin (Eomes), Granzyme B, and perforin, after cultivation, and exhibit cytotoxic function, suggesting that CRTAM(+) T cells are the precursor of CD4(+)CTL. Indeed, ectopic expression of CRTAM in T cells induced the production of IFN-γ, expression of CTL-related genes, and cytotoxic activity. The induction of CD4(+)CTL and IFN-γ production requires CRTAM-mediated intracellular signaling. CRTAM(+) T cells traffic to mucosal tissues and inflammatory sites and developed into CD4(+)CTL, which are involved in mediating protection against infection as well as inducing inflammatory response, depending on the circumstances, through IFN-γ secretion and cytotoxic activity. These results reveal that CRTAM is critical to instruct the differentiation of CD4(+)CTL through the induction of Eomes and CTL-related gene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Differentiation
  • Cell Line
  • Cell Movement / genetics
  • Cell Movement / immunology
  • Colitis / genetics
  • Colitis / immunology
  • Colitis / pathology
  • Gene Expression Regulation
  • Humans
  • Immunoglobulins / genetics*
  • Immunoglobulins / metabolism
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / metabolism
  • Interferon-gamma / biosynthesis
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Mucous Membrane / immunology
  • Mucous Membrane / metabolism
  • Mucous Membrane / pathology
  • Phenotype
  • T-Box Domain Proteins / metabolism
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism*
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / metabolism*

Substances

  • Immunoglobulins
  • T-Box Domain Proteins
  • class-I restricted T cell-associated molecule
  • Interferon-gamma