1. IL-6-Driven pSTAT1 Response Is Linked to T Cell Features Implicated in Early Immune Dysregulation
- Author
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Lambert, Katharina, Diggins, Kirsten E, Jones, Britta E, Hundhausen, Christian, Maerz, Megan D, Hocking, Anne M, Sanda, Srinath, Greenbaum, Carla J, Linsley, Peter S, Cerosaletti, Karen, and Buckner, Jane H
- Subjects
Biomedical and Clinical Sciences ,Immunology ,Autoimmune Disease ,Aetiology ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,Apoptosis ,Cytokines ,Humans ,Immune System Diseases ,Interleukin-6 ,STAT1 Transcription Factor ,Signal Transduction ,T-Lymphocytes ,interleukin-6 ,interleukin-6 receptor ,T cells ,STAT1 ,STAT3 ,apoptosis ,autoimmunity ,Medical Microbiology ,Biochemistry and cell biology ,Genetics - Abstract
Elevated levels and enhanced sensing of the pro-inflammatory cytokine interleukin-6 (IL-6) are key features of many autoimmune and inflammatory diseases. To better understand how IL-6 signaling may influence human T cell fate, we investigated the relationships between levels of components of the IL-6R complex, pSTAT responses, and transcriptomic and translational changes in CD4+ and CD8+ T cell subsets from healthy individuals after exposure to IL-6. Our findings highlight the striking heterogeneity in mbIL-6R and gp130 expression and IL-6-driven pSTAT1/3 responses across T cell subsets. Increased mbIL-6R expression correlated with enhanced signaling via pSTAT1 with less impact on pSTAT3, most strikingly in CD4+ naïve T cells. Additionally, IL-6 rapidly induced expression of transcription factors and surface receptors expressed by T follicular helper cells and altered expression of markers of apoptosis. Importantly, many of the features associated with the level of mbIL-6R expression on T cells were recapitulated both in the setting of tocilizumab therapy and when comparing donor CD4+ T cells harboring the genetic variant, IL6R Asp358Ala (rs2228145), known to alter mbIL-6R expression on T cells. Collectively, these findings should be taken into account as we consider the role of IL-6 in disease pathogenesis and translating IL-6 biology into effective therapies for T cell-mediated autoimmune disease.
- Published
- 2022