Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612, USA.
J Immunol. 2013 Jun 1;190(11):5516-25. doi: 10.4049/jimmunol.1202298. Epub 2013 Apr 29.
Earlier, we had demonstrated that treatment with low dose of GM-CSF can prevent the development of experimental autoimmune thyroiditis (EAT), experimental autoimmune myasthenia gravis, and type 1 diabetes, and could also reverse ongoing EAT and experimental autoimmune myasthenia gravis. The protective effect was mediated through the induction of tolerogenic CD11C(+)CD8α(-) dendritic cells (DCs) and consequent expansion of Foxp3(+) regulatory T cells (Tregs). Subsequently, we showed that GM-CSF acted specifically on bone marrow precursors and facilitated their differentiation into tolerogenic dendritic cells (DCs; GM-CSF-induced bone marrow-derived DCs [GM-BMDCs]), which directed Treg expansion in a contact-dependent manner. This novel mechanism of Treg expansion was independent of TCR-mediated signaling but required exogenous IL-2 and cosignaling from DC-bound OX40L. In this study, we observed that OX40L-mediated signaling by GM-BMDCs, although necessary, was not sufficient for Treg expansion and required signaling by Jagged1. Concurrent signaling induced by OX40L and Jagged1 via OX40 and Notch3 receptors expressed on Tregs was essential for the Treg expansion with sustained FoxP3 expression. Adoptive transfer of only OX40L(+)Jagged1(+) BMDCs led to Treg expansion, increased production of IL-4 and IL-10, and suppression of EAT in the recipient mice. These results showed a critical role for OX40L- and Jagged1-induced cosignaling in GM-BMDC-induced Treg expansion.
早些时候，我们已经证明，低剂量 GM-CSF 的治疗可以预防实验性自身免疫性甲状腺炎（EAT）、实验性自身免疫性重症肌无力和 1 型糖尿病的发生，并且还可以逆转正在进行的 EAT 和实验性自身免疫性重症肌无力。这种保护作用是通过诱导耐受性 CD11C(+)CD8α(-)树突状细胞（DC）和随后的 Foxp3(+)调节性 T 细胞（Tregs）的扩增来介导的。随后，我们表明 GM-CSF 特异性作用于骨髓前体并促进其分化为耐受性树突状细胞（DC；GM-CSF 诱导的骨髓源性 DC [GM-BMDCs]），以接触依赖性方式指导 Treg 的扩增。这种 Treg 扩增的新机制独立于 TCR 介导的信号转导，但需要外源性 IL-2 和 DC 结合的 OX40L 的共信号。在这项研究中，我们观察到 GM-BMDC 上的 OX40L 介导的信号虽然是必需的，但不足以进行 Treg 的扩增，并且需要 Jagged1 上的信号。Tregs 上表达的 OX40 和 Notch3 受体通过 OX40L 和 Jagged1 诱导的共信号对于 Treg 的扩增和持续的 FoxP3 表达是必不可少的。仅 OX40L(+)Jagged1(+)BMDC 的过继转移导致 Treg 的扩增、IL-4 和 IL-10 的产生增加，并抑制受体小鼠中的 EAT。这些结果表明，OX40L 和 Jagged1 诱导的共信号在 GM-BMDC 诱导的 Treg 扩增中起着关键作用。
