IL-4 triggers autoimmune diabetes by increasing self-antigen presentation within the pancreatic Islets.
Several findings have recently questioned the long held hypothesis that cytokines belonging to the Th2 pathway are protective in T-cell-mediated autoimmunity. Among them, there is our previous report that pancreatic expression of IL-4 activated islet antigen-specific BDC2.5 T cells and rendered them able to trigger insulin-dependent diabetes mellitus in ins-IL-4/BDC2.5 mice (Mueller et al., Immunity, 7, 1997). Here we analyze the mechanisms underlying IL-4-mediated activation of the self-reactive BDC2.5 T cells. IL-4 is mainly known as the Th2-driving cytokine. However, IL-4 is also critical for DC maturation and upregulation of antigen uptake and presentation by macrophages. In our model, we found that pancreatic expression of IL-4 activated self-reactive BDC2.5 T cells by increasing islet antigen presentation by macrophages and dendritic cells. IL-4 could have triggered self-antigen presentation within the pancreatic islets both by driving maturation of DC from a tolerizing to a priming state and by increasing self-antigen uptake by macrophages.
Falcone
M
M
Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California, 92037, USA.
Yeung
B
B
Tucker
L
L
Rodriguez
E
E
Krahl
T
T
Sarvetnick
N
N
D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects*; D001324:Autoantigens / Q000276:immunology*; D001327:Autoimmune Diseases / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance / Q000502:physiology; D015847:Interleukin-4 / Q000494:pharmacology / Q000633:toxicity*; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D018448:Models, Immunological; D011994:Recombinant Proteins / Q000494:pharmacology / Q000633:toxicity; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology
D001324:Autoantigens; D011994:Recombinant Proteins; D015847:Interleukin-4