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.
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.
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作者：
Bertin-Maghit S;Pang D;O'Sullivan B;Best S;Duggan E;Paul S;Thomas H;Kay TW;Harrison LC;Steptoe R;Thomas R
免疫耐受策略的有效性，如抗CD 40 L或树突状细胞（DC），是更大的年轻非肥胖糖尿病（NOD）小鼠时，比高峰胰岛炎。在核因子-κB抑制剂存在下产生的RelBlo DC诱导T调节（Treg）细胞并抑制类风湿性关节炎模型中的炎症。白细胞介素（IL）-1β在有1型糖尿病风险的人类和小鼠中过表达，调节性T细胞失调，并加速NOD小鼠的糖尿病。我们研究了在糖尿病前期IL-1β产生与RelBlo DCs反应之间的关系。我们将RelBlo DC皮下注射到4或14周龄的NOD小鼠中，并跟踪糖尿病的发病率和对Treg细胞功能的影响。我们测量了不同年龄和品系小鼠的刺激脾细胞和未刺激胰岛的促炎细胞因子的表达，以及T效应细胞对Treg的体外增殖和细胞因子应答。耐受RelBlo DCs显著抑制糖尿病进展时，给予4周龄，但不是14周龄的小鼠。当主要组织相容性复合体（MHC）限制性胰岛抗原呈递给自身反应性T细胞时，NOD脾细胞的IL-1β产生和胰岛的mRNA表达从6至16周龄增加。IL-1降低了Treg细胞抑制效应细胞的能力，并促进其转化为Th 17细胞。RelBlo DC加剧了Treg功能的IL-1依赖性下降，并促进了Th 17转化。由MHC易感小鼠中的胰岛自身反应性细胞产生的IL-1β通过以Treg为代价分化Th 17来加速糖尿病。耐受DC疗法可以调节胰岛自身抗原引发并预防糖尿病，但超过IL-1β/IL-17检查点的进展表明需要其他策略。
The effectiveness of tolerizing immunotherapeutic strategies, such as anti-CD40L or dendritic cells (DCs), is greater when administered to young nonobese diabetic (NOD) mice than at peak insulitis. RelBlo DCs, generated in the presence of an nuclear factor-κB 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 RelBlo DCs in the prediabetic period. We injected RelBlo 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. Tolerizing RelBlo 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 histocompatibility 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 Th17 cells. RelBlo DCs exacerbated the IL-1–dependent decline in Treg function and promoted Th17 conversion. IL-1β, generated by islet-autoreactive cells in MHC-susceptible mice, accelerates diabetes by differentiating Th17 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.