STAT5B: A Differential Regulator of the Life and Death of CD4 + Effector Memory T Cells

J Immunol. 2018 Jan 1;200(1):110-118. doi: 10.4049/jimmunol.1701133. Epub 2017 Nov 29.

Abstract

Understanding the control of Ag restimulation-induced T cell death (RICD), especially in cancer immunotherapy, where highly proliferating T cells will encounter potentially large amounts of tumor Ags, is important now more than ever. It has been known that growth cytokines make T cells susceptible to RICD, but the precise molecular mediators that govern this in T cell subsets is unknown until now. STAT proteins are a family of transcription factors that regulate gene expression programs underlying key immunological processes. In particular, STAT5 is known to favor the generation and survival of memory T cells. In this study, we report an unexpected role for STAT5 signaling in the death of effector memory T (TEM) cells in mice and humans. TEM cell death was prevented with neutralizing anti-IL-2 Ab or STAT5/JAK3 inhibitors, indicating that STAT5 signaling drives RICD in TEM cells. Moreover, we identified a unique patient with a heterozygous missense mutation in the coiled-coil domain of STAT5B that presented with autoimmune lymphoproliferative syndrome-like features. Similar to Stat5b-/- mice, this patient exhibited increased CD4+ TEM cells in the peripheral blood. The mutant STAT5B protein dominantly interfered with STAT5-driven transcriptional activity, leading to global downregulation of STAT5-regulated genes in patient T cells upon IL-2 stimulation. Notably, CD4+ TEM cells from the patient were strikingly resistant to cell death by in vitro TCR restimulation, a finding that was recapitulated in Stat5b-/- mice. Hence, STAT5B is a crucial regulator of RICD in memory T cells in mice and humans.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Neutralizing / metabolism
  • Apoptosis*
  • Autoimmune Lymphoproliferative Syndrome / genetics
  • Autoimmune Lymphoproliferative Syndrome / immunology*
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Survival*
  • Cells, Cultured
  • Female
  • Humans
  • Immunologic Memory
  • Interleukin-2 / immunology
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation, Missense / genetics
  • STAT5 Transcription Factor / genetics
  • STAT5 Transcription Factor / metabolism*
  • Signal Transduction
  • Transcription, Genetic

Substances

  • Antibodies, Neutralizing
  • Interleukin-2
  • STAT5 Transcription Factor