To understand the mechanism underlying antigen restimulation-induced T cell death (RICD), a critical control to dampen T cell effector memory (TEM) levels, Majri et al. observed that STAT5B signaling drives RICD in TEM cells. A genetic screen of a patient with an autoimmune disorder revealed a missense mutation in the dimerization domain of STAT5B, causing lack of transcriptional activity. The patient’s CD4+ TEM cells were significantly increased and were highly resistant to cell death by in vitro TCR restimulation.

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.

Author Info: (1) Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

Author Info: (1) Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892. Ecole Doctorale Hematologie-Oncogenese-Biotherapies, Universite Paris-Diderot, Paris, France 75475. National Institute of Allergy and Infectious Diseases Clinical Genomics Program, National Institutes of Health, Bethesda, MD 20892. (2) Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892. National Institute of Allergy and Infectious Diseases Clinical Genomics Program, National Institutes of Health, Bethesda, MD 20892. (3) Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD (4) Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892. National Institute of Allergy and Infectious Diseases Clinical Genomics Program, National Institutes of Health, Bethesda, MD 20892. (5) Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892. National Institute of Allergy and Infectious Diseases Clinical Genomics Program, National Institutes of Health, Bethesda, MD 20892. (6) Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892. National Institute of Allergy and Infectious Diseases Clinical Genomics Program, National Institutes of Health, Bethesda, MD 20892. (7) Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892. National Institute of Allergy and Infectious Diseases Clinical Genomics Program, National Institutes of Health, Bethesda, MD 20892. (8) Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892. (9) Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD (10) Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892. National Institute of Allergy and Infectious Diseases Clinical Genomics Program, National Institutes of Health, Bethesda, MD 20892. (11) Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892. (12) Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and. (13) Institut Mondor de Recherche Biomedicale, INSERM U955, Creteil, France 94000. (14) National Institute of Allergy and Infectious Diseases Clinical Genomics Program, National Institutes of Health, Bethesda, MD 20892. Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and. (15) Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD (16) National Institute of Allergy and Infectious Diseases Clinical Genomics Program, National Institutes of Health, Bethesda, MD 20892. Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and. (17) Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; Lenardo@nih.gov. National Institute of Allergy and Infectious Diseases Clinical Genomics Program, National Institutes of Health, Bethesda, MD 20892.

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