Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; St. Jude Graduate School of Biomedical Sciences, Memphis, TN 38105, USA.
Cell Rep. 2023 Feb 28;42(2):112106. doi: 10.1016/j.celrep.2023.112106. Epub 2023 Feb 13.
Drak2-deficient (Drak2) mice are resistant to multiple models of autoimmunity yet effectively eliminate pathogens and tumors. Thus, DRAK2 represents a potential target to treat autoimmune diseases. However, the mechanisms by which DRAK2 contributes to autoimmunity, particularly type 1 diabetes (T1D), remain unresolved. Here, we demonstrate that resistance to T1D in non-obese diabetic (NOD) mice is due to the absence of Drak2 in T cells and requires the presence of regulatory T cells (T). Contrary to previous hypotheses, we show that DRAK2 does not limit TCR signaling. Rather, DRAK2 regulates IL-2 signaling by inhibiting STAT5A phosphorylation. We further demonstrate that enhanced sensitivity to IL-2 in the absence of Drak2 augments thymic T development. Overall, our data indicate that DRAK2 contributes to autoimmunity in multiple ways by regulating thymic T development and by impacting the sensitivity of conventional T cells to T-mediated suppression.
Drak2 缺陷（Drak2）小鼠对多种自身免疫模型具有抗性，但能有效消除病原体和肿瘤。因此，DRAK2 代表了治疗自身免疫疾病的潜在靶点。然而，DRAK2 如何导致自身免疫的机制，特别是 1 型糖尿病（T1D），仍未解决。在这里，我们证明非肥胖型糖尿病（NOD）小鼠对 T1D 的抗性是由于 T 细胞中缺乏 Drak2，并且需要调节性 T 细胞（T）的存在。与之前的假设相反，我们表明 DRAK2 不会限制 TCR 信号。相反，DRAK2 通过抑制 STAT5A 磷酸化来调节 IL-2 信号。我们进一步证明，在缺乏 Drak2 的情况下，IL-2 敏感性的增强会增强胸腺 T 细胞的发育。总体而言，我们的数据表明 DRAK2 通过调节胸腺 T 细胞的发育以及影响常规 T 细胞对 T 细胞介导的抑制的敏感性，以多种方式导致自身免疫。
