OX40L/Jagged1 cosignaling by GM-CSF-induced bone marrow-derived dendritic cells is required for the expansion of functional regulatory T cells.
OX40L/Jagged1 cosignaling by GM-CSF-induced bone marrow-derived dendritic cells is required for the expansion of functional regulatory T cells.
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DOI：
10.4049/jimmunol.1202298
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发表时间：
2013-06-01
期刊：
影响因子：
--
通讯作者：
Prabhakar BS
中科院分区：
文献类型：
--
作者：
Gopisetty A;Bhattacharya P;Haddad C;Bruno JC Jr;Vasu C;Miele L;Prabhakar BS
早些时候，我们已经证明，用低剂量的GM-CSF治疗可以预防实验性自身免疫性甲状腺炎（EAT）、重症肌无力（EAMG）和1型糖尿病的发展;并且还可以逆转正在进行的EAT和EAMG。这种保护作用是通过诱导致耐受性CD 11 C + CD 8 α− DCs和随后的Foxp 3 + T调节细胞（TCFs）扩增来介导的。随后，我们发现GM-CSF特异性作用于骨髓前体，并促进其分化为致耐受性DC（GM-BMDC），其以接触依赖性方式指导Treg扩增。这种Treg扩增的新机制不依赖于TCR介导的信号传导，但需要外源性IL-2和来自DC结合的0X 40 L的共信号传导。在本研究中，我们观察到，OX 40 L介导的GM-BMDCs的信号传导虽然是必要的，但对于Treg扩增是不够的，需要Jagged 1的信号传导。由OX 40 L和Jagged 1通过TcB上表达的OX 40和Notch 3受体诱导的并行信号传导对于Treg扩增和持续的FoxP 3表达是必需的。仅OX 40 L + Jagged 1 + BMDC的连续转移导致受体小鼠中Treg扩增、IL-4和IL-10的产生增加以及EAT的抑制。这些结果显示了0X 40 L和Jagged 1诱导的共信号传导在GM-BMDC诱导的Treg扩增中的关键作用。
Earlier, we had demonstrated that treatment with low dose of GM-CSF can prevent the development of experimental autoimmune thyroiditis (EAT), myasthenia gravis (EAMG) and type-1 diabetes; and could also reverse ongoing EAT and EAMG. The protective effect was mediated through the induction of tolerogenic CD11C+CD8α− DCs and consequent expansion of Foxp3+ T-regulatory cells (Tregs). Subsequently, we showed that GM-CSF acted specifically on bone marrow precursors and facilitated their differentiation into tolerogenic DCs (GM-BMDCs), which directed Treg expansion in a contact dependent manner. This novel mechanism of Treg expansion was independent of TCR mediated signalling but required exogenous IL-2 and co-signalling from DC bound OX40L. In the present study, we observed that OX40L mediated signalling by GM-BMDCs although necessary was not sufficient for Treg expansion and required signalling by Jagged1. Concurrent signalling 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 co-signalling in GM-BMDC-induced Treg expansion.
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鉴定人OX-40配体，这是具有与肿瘤坏死因子同源的CD4+ T细胞的costimulator。
影响因子：
15.3
作者：
Godfrey, Wayne R.;Fagnoni, Francesco F.;Haraa, Marwan A.;Buck, David;Engleman, Edgar G.
通讯作者：
Engleman, Edgar G.
DOI：
10.1084/jem.161.1.72
发表时间：
1985-01-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Sakaguchi S;Fukuma K;Kuribayashi K;Masuda T
通讯作者：
Masuda T
DOI：
10.4049/jimmunol.0901112
发表时间：
2009-10-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Ruby CE;Yates MA;Hirschhorn-Cymerman D;Chlebeck P;Wolchok JD;Houghton AN;Offner H;Weinberg AD
通讯作者：
Weinberg AD
影响因子：
20.3
作者：
Samon, Jeremy B.;Champhekar, Ameya;Osborne, Barbara A.
通讯作者：
Osborne, Barbara A.
影响因子：
30.5
作者：
Minter, LM;Turley, DM;Osborne, BA
通讯作者：
Osborne, BA