Interleukin-4 regulates eomesodermin in CD8+ T cell development and differentiation

PLoS One. 2014 Sep 10;9(9):e106659. doi: 10.1371/journal.pone.0106659. eCollection 2014.

Abstract

Interleukin (IL)-4 is a cytokine classically associated with CD4(+) T helper type 2 differentiation, but has been recently shown to also be required for the development of CD8(+) innate-like lymphocytes. CD8(+) innate-like lymphocytes are non-conventional lymphocytes that exhibit characteristics typically associated with memory CD8(+) T cells, including expression of the T-box transcription factor Eomesodermin (Eomes). Here we investigate the signaling pathways required for IL-4 induction of Eomes and CD8(+) innate-like lymphocyte markers in murine CD8SP thymocytes and peripheral CD8(+) T cells. We demonstrate that IL-4 is sufficient to drive Eomes expression and the CD8(+) innate-like lymphocyte phenotype through cooperation between STAT6- and Akt-dependent pathways. Furthermore, we show that while IL-4 has little effect on the induction of Eomes in the setting of robust T cell receptor (TCR) activation, this cytokine promotes Eomes in the setting of attenuated TCR stimulation in mature CD8(+) T cells suggesting that cytokine signaling pathways may direct cell fate when TCR signals are limiting.

Publication types

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

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / cytology*
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Differentiation / drug effects*
  • Interferon-gamma / metabolism
  • Interleukin-4 / pharmacology*
  • Mice
  • Phenotype
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Antigen, T-Cell / metabolism
  • STAT6 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • T-Box Domain Proteins / metabolism*
  • Thymocytes / immunology
  • Up-Regulation / drug effects

Substances

  • Eomes protein, mouse
  • Receptors, Antigen, T-Cell
  • STAT6 Transcription Factor
  • T-Box Domain Proteins
  • Interleukin-4
  • Interferon-gamma
  • Proto-Oncogene Proteins c-akt