Enhanced T cell responses to IL-6 in type 1 diabetes are associated with early clinical disease and increased IL-6 receptor expression
| Autor: | Stephen P. Evanko, Rebecca Rawlings, Christian Hundhausen, Anya Schneider, Janice Chen, Thomas N. Wight, Mackenzie Kinsman, S. Alice Long, Karen Cerosaletti, Alena Roth, Elizabeth Whalen, Shan Wei, Jane H. Buckner, Carla J. Greenbaum |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Adult Male STAT3 Transcription Factor medicine.medical_treatment T cell Receptor expression T-Lymphocytes C-C chemokine receptor type 7 Autoimmunity In Vitro Techniques medicine.disease_cause Translational Research Biomedical 03 medical and health sciences Young Adult 0302 clinical medicine Cell Movement Cytotoxic T cell Medicine Humans STAT1 Interleukin 6 biology business.industry Interleukin-6 Gene Expression Profiling General Medicine Middle Aged Receptors Interleukin-6 030104 developmental biology Cytokine medicine.anatomical_structure Diabetes Mellitus Type 1 Case-Control Studies Immunology biology.protein Commentary Female business 030215 immunology Signal Transduction |
| Zdroj: | Science translational medicine. 8(356) |
| ISSN: | 1946-6242 |
| Popis: | Interleukin-6 (IL-6) is a key pathogenic cytokine in multiple autoimmune diseases including rheumatoid arthritis and multiple sclerosis, suggesting that dysregulation of the IL-6 pathway may be a common feature of autoimmunity. The role of IL-6 in type 1 diabetes (T1D) is not well understood. We show that signal transducer and activator of transcription 3 (STAT3) and STAT1 responses to IL-6 are significantly enhanced in CD4 and CD8 T cells from individuals with T1D compared to healthy controls. The effect is IL-6–specific because it is not seen with IL-10 or IL-27 stimulation, two cytokines that signal via STAT3. An important determinant of enhanced IL-6 responsiveness in T1D is IL-6 receptor surface expression, which correlated with phospho-STAT3 levels. Further, reduced expression of the IL-6R sheddase ADAM17 in T cells from patients indicated a mechanistic link to enhanced IL-6 responses in T1D. IL-6–induced STAT3 phosphorylation was inversely correlated with time from diagnosis, suggesting that dysregulation of IL-6 signaling may be a marker of early disease. Finally, whole-transcriptome analysis of IL-6–stimulated CD4 + T cells from patients revealed previously unreported IL-6 targets involved in T cell migration and inflammation, including lymph node homing markers CCR7 and L-selectin. In summary, our study demonstrates enhanced T cell responses to IL-6 in T1D due, in part, to an increase in IL-6R surface expression. Dysregulated IL-6 responsiveness may contribute to diabetes through multiple mechanisms including altered T cell trafficking and indicates that individuals with T1D may benefit from IL-6–targeted therapeutic intervention such as the one that is being currently tested (NCT02293837). |
| Databáze: | OpenAIRE |
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