Islet antigen-specific Th17 cells can induce TNF-α-dependent autoimmune diabetes.
Type 1 diabetes (T1D) results from autoimmune destruction of pancreatic β-cells. Although Th1 cells are key orchestrators of T1D, the function(s) of the more recently identified Th17 subset are unclear due to inherent plasticity. In this study, we analyzed Th17 cells for stability and diabetogenicity in NOD mice. We found that like Th1 cells, Th17 are a distinct population throughout the prediabetic phase. At diabetes onset, there were marked increases in IL-17-producing Th17 cells and IFN-γ-producing Th1 cells in the pancreas as well as in the serum levels of these cytokines, indicating that these proinflammatory mediators serve as biomarkers of advanced autoimmunity. Although naturally occurring Th17 cells in diabetic mice did not contribute to diabetes development in transfer models, islet-specific Th17 cells were diabetogenic independently of IL-17 and displayed inflammation-induced Th17-to-Th1 reprogramming that could be elicited by Th1 cells. However, an inability to generate Th1 cells because of Stat4, Ifngr, and Ifng deficiencies did not prevent diabetes. Instead, TNF-α could mediate diabetes in response to either Th17 cells or Th1 cells. The results identify a previously unknown mechanism by which Th17 cells can contribute to T1D. Our studies also suggest that when developing interventions for T1D, it will be potentially advantageous to focus on mechanisms common to effector T cells rather than on the signature cytokines of various subsets.
Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
Cheng-Rui
CR
Li
Erin E
EE
Mueller
Linda M
LM
Bradley
D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D050417:Insulin-Secreting Cells / Q000276:immunology*; D007371:Interferon-gamma / Q000097:blood / Q000235:genetics / Q000378:metabolism; D020381:Interleukin-17 / Q000097:blood / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010179:Pancreas / Q000276:immunology; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics; D050797:STAT4 Transcription Factor / Q000172:deficiency / Q000235:genetics; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D000096743:Interferon gamma Receptor
D015415:Biomarkers; D007371:Interferon-gamma; D020381:Interleukin-17; D017471:Receptors, Interferon; D050797:STAT4 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D000096743:Interferon gamma Receptor; C098680:Il17a protein, mouse; C494091:Stat4 protein, mouse