STAT5B: A differential regulator of the life and death of CD4+ effector memory T cells

Sonia S. Majri, Jill M. Fritz, Alejandro V. Villarino, Lixin Zheng, Chrysi Kanellopoulou, Benjamin Chaigne-Delalande, Juha Grönholm, Julie E. Niemela, Behdad Afzali, Matthew Biancalana, Stefania Pittaluga, Ashleigh Sun, José L. Cohen, Steven M. Holland, John J. O'Shea, Gulbu Uzel, Michael J. Lenardo

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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 afamily 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.

Original languageEnglish (US)
Pages (from-to)110-118
Number of pages9
JournalJournal of Immunology
Volume200
Issue number1
DOIs
StatePublished - Jan 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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