In:
The Journal of Immunology, The American Association of Immunologists, Vol. 200, No. 1 ( 2018-01-01), p. 110-118
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.
Type of Medium:
Online Resource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.1701133
Language:
English
Publisher:
The American Association of Immunologists
Publication Date:
2018
detail.hit.zdb_id:
1475085-5
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