Dataset Information

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

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.

SUBMITTER: Majri SS

PROVIDER: S-EPMC5736408 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Publications

STAT5B: A Differential Regulator of the Life and Death of CD4<sup>+</sup> Effector Memory T Cells.

Majri Sonia S SS Fritz Jill M JM Villarino Alejandro V AV Zheng Lixin L Kanellopoulou Chrysi C Chaigne-Delalande Benjamin B Grönholm Juha J Niemela Julie E JE Afzali Behdad B Biancalana Matthew M Pittaluga Stefania S Sun Ashleigh A Cohen José L JL Holland Steven M SM O'Shea John J JJ Uzel Gulbu G Lenardo Michael J MJ

Journal of immunology (Baltimore, Md. : 1950) 20171129 1

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 underlyi ...[more]

PMID: 29187589

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Project description:Trichloroethylene (TCE) is an industrial solvent and drinking water pollutant associated with CD4+ T cell-mediated autoimmunity. In our mouse model, discontinuation of TCE exposure during adulthood after developmental exposure did not prevent immunotoxicity. To determine whether persistent effects were linked to epigenetic changes we conducted whole genome reduced representation bisulfite sequencing (RRBS) to evaluate methylation of CpG sites in autosomal chromosomes in activated effector/memory CD4+ T cells. Female MRL+/+ mice were exposed to vehicle control or TCE in the drinking water from gestation until ~37 weeks of age [postnatal day (PND) 259]. In a subset of mice, TCE exposure was discontinued at ~22 weeks of age (PND 154). At PND 259, RRBS assessment revealed more global methylation changes in the continuous exposure group vs. the discontinuous exposure group. A majority of the differentially methylated CpG regions (DMRs) across promoters, islands, and regulatory elements were hypermethylated (~90%). However, continuous developmental TCE exposure altered the methylation of 274 CpG sites in promoters and CpG islands. In contrast, only 4 CpG island regions were differentially methylated (hypermethylated) in the discontinuous group. Interestingly, 2 of these 4 sites were also hypermethylated in the continuous exposure group, and both of these island regions are associated with lysine 27 on histone H3 (H3K27) involved in polycomb complex-dependent transcriptional repression via H3K27 tri-methylation. CpG sites were overlapped with the Open Regulatory Annotation database. Unlike the discontinuous group, continuous TCE treatment resulted in 129 DMRs including 12 unique transcription factors and regulatory elements; 80% of which were enriched for one or more polycomb group (PcG) protein binding regions (i.e., SUZ12, EZH2, JARID2, and MTF2). Pathway analysis of the DMRs indicated that TCE primarily altered the methylation of genes associated with regulation of cellular metabolism and cell signaling. The results demonstrated that continuous developmental exposure to TCE differentially methylated binding sites of PcG proteins in effector/memory CD4+ cells. There were minimal yet potentially biologically significant effects that occurred when exposure was discontinued. These results point toward a novel mechanism by which chronic developmental TCE exposure may alter terminally differentiated CD4+ T cell function in adulthood.

Dataset Information

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

Publications

STAT5B: A Differential Regulator of the Life and Death of CD4<sup>+</sup> Effector Memory T Cells.

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