TRAF2 regulates peripheral CD8(+) T-cell and NKT-cell homeostasis by modulating sensitivity to IL-15

Eur J Immunol. 2015 Jun;45(6):1820-31. doi: 10.1002/eji.201445416. Epub 2015 May 26.

Abstract

In this study, a critical and novel role for TNF receptor (TNFR) associated factor 2 (TRAF2) is elucidated for peripheral CD8(+) T-cell and NKT-cell homeostasis. Mice deficient in TRAF2 only in their T cells (TRAF2TKO) show ∼40% reduction in effector memory and ∼50% reduction in naïve CD8(+) T-cell subsets. IL-15-dependent populations were reduced further, as TRAF2TKO mice displayed a marked ∼70% reduction in central memory CD8(+) CD44(hi) CD122(+) T cells and ∼80% decrease in NKT cells. TRAF2TKO CD8(+) CD44(hi) T cells exhibited impaired dose-dependent proliferation to exogenous IL-15. In contrast, TRAF2TKO CD8(+) T cells proliferated normally to anti-CD3 and TRAF2TKO CD8(+) CD44(hi) T cells exhibited normal proliferation to exogenous IL-2. TRAF2TKO CD8(+) T cells expressed normal levels of IL-15-associated receptors and possessed functional IL-15-mediated STAT5 phosphorylation, however TRAF2 deletion caused increased AKT activation. Loss of CD8(+) CD44(hi) CD122(+) and NKT cells was mechanistically linked to an inability to respond to IL-15. The reduced CD8(+) CD44(hi) CD122(+) T-cell and NKT-cell populations in TRAF2TKO mice were rescued in the presence of high dose IL-15 by IL-15/IL-15Rα complex administration. These studies demonstrate a critical role for TRAF2 in the maintenance of peripheral CD8(+) CD44(hi) CD122(+) T-cell and NKT-cell homeostasis by modulating sensitivity to T-cell intrinsic growth factors such as IL-15.

Keywords: CD8+ T cell; Homeostasis; IL-15; NKT cell; TRAF2; TRAF3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / physiology*
  • Cellular Microenvironment
  • Cytokines / pharmacology
  • Female
  • Gene Expression
  • Homeostasis*
  • Immunologic Memory
  • Immunophenotyping
  • Interleukin-15 / pharmacology*
  • Lymphocyte Count
  • Lymphopenia / genetics
  • Lymphopenia / immunology
  • Lymphopenia / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Natural Killer T-Cells / drug effects*
  • Natural Killer T-Cells / physiology*
  • Phenotype
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Interleukin-15 / genetics
  • Receptors, Interleukin-15 / metabolism
  • Signal Transduction
  • T-Lymphocyte Subsets / drug effects
  • T-Lymphocyte Subsets / physiology
  • TNF Receptor-Associated Factor 2 / genetics*
  • TNF Receptor-Associated Factor 2 / metabolism
  • TNF Receptor-Associated Factor 3 / genetics
  • TNF Receptor-Associated Factor 3 / metabolism

Substances

  • Cytokines
  • Interleukin-15
  • NF-kappa B
  • Receptors, Interleukin-15
  • TNF Receptor-Associated Factor 2
  • TNF Receptor-Associated Factor 3
  • Proto-Oncogene Proteins c-akt