Interleukin-1β Produced in Response to Islet Autoantigen Presentation Differentiates T-Helper 17 Cells at the Expense of Regulatory T-Cells Implications for the Timing of Tolerizing Immunotherapy

摘要

Objective-the effectiveness of tolerizing immunotherapeu-tic strategies, such as anti-cd40l or dendritic cells (dcs), is greater when administered to young nonobese diabetic (nod) mice than at peak insulitis. Relb~(lo) dcs, generated in the presence of an nuclear factor-kb inhibitor, induce t-regulatory (treg) cells and suppress inflammation in a model of rheumatoid arthritis. Interleukin (il)-1β is overexpressed in humans and mice at risk of type 1 diabetes, dysregulates treg cells, and accelerates diabetes in nod mice. We investigated the relationship between il-1β production and the response to relb10 dcs in the predia-betic period. Research design and methods-we injected relb~(lo) dcs subcutaneously into 4- or 14-week-old nod mice and tracked the incidence of diabetes and effect on treg cell function. We measured the expression of proinflammatory cytokines by stimulated splenocytes and unstimulated islets from mice of different ages and strains and proliferative and cytokine responses of t effectors to treg in vitro. Results-tolerizing relb10 dcs significantly inhibited diabetes progression when administered to 4-week-old but not 14-week-old mice. Il-1β production by nod splenocytes and mrna expression by islets increased from 6 to 16 weeks of age when major histocom-patibility complex (mhc)-restricted islet antigen presentation to autoreactive t-cells occurred. Il-1 reduced the capacity of treg cells to suppress effector cells and promoted their conversion to thl7 cells. Relb10 dcs exacerbated the il-1-dependent decline in treg function and promoted thl7 conversion. Conclusions-il-113, generated by islet-autoreactive cells in mhc-susceptible mice, accelerates diabetes by differentiating thl7 at the expense of treg. Tolerizing dc therapies can regulate islet autoantigen priming and prevent diabetes, but progression past the il-1β/il-17 checkpoint signals the need for other strategies. Diabetes 60:248-257, 2011