It has proven difficult to identify the underlying genes in complex autoimmune diseases. Here, we use forward genetics to identify polymorphisms in the vitamin D receptor gene (Vdr) promoter, controlling Vdr expression and T cell activation. We isolated these polymorphisms in a congenic mouse line, allowing us to study the immunomodulatory properties of VDR in a physiological context. Congenic mice overexpressed VDR selectively in T cells, and thus did not suffer from calcemic effects. VDR overexpression resulted in an enhanced antigen-specific T cell response and more severe autoimmune phenotypes. In contrast, vitamin D3-deficiency inhibited T cell responses and protected mice from developing autoimmune arthritis. Our observations are likely translatable to humans, as Vdr is overexpressed in rheumatic joints. Genetic control of VDR availability codetermines the proinflammatory behavior of T cells, suggesting that increased presence of VDR at the site of inflammation might limit the antiinflammatory properties of its ligand.

已证明很难鉴定复杂的自身免疫性疾病的潜在基因。在这里，我们使用正向遗传学来识别维生素D受体基因（Vdr）启动子中的多态性，控制Vdr的表达和T细胞的活化。我们在同系小鼠品系中分离了这些多态性，从而使我们能够在生理背景下研究VDR的免疫调节特性。同基因小鼠在T细胞中选择性过表达VDR，因此没有钙减少作用。VDR过表达导致增强的抗原特异性T细胞反应和更严重的自身免疫表型。相反，维生素D3缺乏会抑制T细胞反应并保护小鼠免于自身免疫性关节炎的发展。我们的观察结果很可能会翻译成人类，因为Vdr在风湿性关节中过表达。VDR可用性的遗传控制决定了T细胞的促炎行为，表明在炎症部位增加VDR的存在可能会限制其配体的抗炎特性。