title: Enhanced T cell responses to IL-6 in type 1 diabetes are associated with early clinical disease and increased IL-6 receptor expression.
abstract: 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).
authors.affiliation: Translational Research Program, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Hundhausen
authors.affiliation: Translational Research Program, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101, USA. Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
authors.forename: Alena
authors.initials: A
authors.lastname: Roth
authors.affiliation: Translational Research Program, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Whalen
authors.affiliation: Translational Research Program, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101, USA.
authors.forename: Janice
authors.initials: J
authors.lastname: Chen
authors.affiliation: Translational Research Program, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101, USA. Neurological Clinic and Clinical Neurophysiology, Central Clinic Augsburg, Stenglinstrasse 2, 86156 Augsburg, Germany.
authors.forename: Anya
authors.initials: A
authors.lastname: Schneider
authors.affiliation: Translational Research Program, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101, USA.
authors.forename: S Alice
authors.initials: SA
authors.lastname: Long
authors.affiliation: Translational Research Program, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Wei
authors.affiliation: Translational Research Program, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Rawlings
authors.affiliation: Translational Research Program, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101, USA.
authors.forename: MacKenzie
authors.initials: M
authors.lastname: Kinsman
authors.affiliation: Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Evanko
authors.affiliation: Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA.
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Wight
authors.affiliation: Diabetes Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA.
authors.forename: Carla J
authors.initials: CJ
authors.lastname: Greenbaum
authors.affiliation: Translational Research Program, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Cerosaletti
authors.affiliation: Translational Research Program, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101, USA. jbuckner@benaroyaresearch.org.
authors.forename: Jane H
authors.initials: JH
authors.lastname: Buckner
mesh_terms: D000328:Adult; D015551:Autoimmunity; D016022:Case-Control Studies; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D057170:Translational Research, Biomedical; D055815:Young Adult
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human