Enhanced engagement of CTLA-4 induces antigen-specific CD4+CD25+Foxp3+ and CD4+CD25- TGF-β1+ adaptive regulatory T cells
Enhanced engagement of CTLA-4 induces antigen-specific CD4+CD25+Foxp3+ and CD4+CD25- TGF-β1+ adaptive regulatory T cells
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DOI：
10.4049/jimmunol.179.8.5191
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发表时间：
2007-10-15
影响因子：
4.4
通讯作者：
Vasu, Chenthamarakshan
中科院分区：
文献类型：
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作者：
Li, Ruobing;Perez, Nicolas;Vasu, Chenthamarakshan
CTLA-4是T细胞反应的关键负性调节因子，在维持免疫耐受中起重要作用。在本文中，我们报道了抗原提呈的树突状细胞增强CTLA-4与T细胞的选择性结合，导致诱导出抗原特异性的CD4(+)CD25(+)Foxp3(+)和CD4(+)CD25(-)转化生长因子-β1(+)适应性树突状细胞。这些细胞是CD62L(低)，对同源抗原刺激反应弱，但与CD62L(高)细胞相比，显示出更强的抑制抗原特异性效应T细胞反应的能力。重要的是，用小鼠甲状腺球蛋白(MTG)冲击的抗CTLA-4激动型抗体包裹的DC治疗自身免疫性甲状腺炎小鼠，这导致CTLA-4在自身抗原呈递上的优势参与，不仅抑制了甲状腺炎，而且防止了MTG再次攻击时疾病的复发。此外，疾病抑制与MTG特异性T细胞和抗体反应显著降低有关。总之，我们的结果显示了选择性CTLA-4信号在诱导适应性Tregs中的重要作用，并建议允许显性CTLA-4结合抗原特异性TCR结扎的方法可以用于靶向治疗。
CTLA-4 is a critical negative regulator of T cell response and is instrumental in maintaining immunological tolerance. In this article, we report that enhanced selective engagement of CTLA-4 on T cells by Ag-presenting dendritic cells resulted in the induction of Ag-specific CD4(+)CD25(+)Foxp3(+) and CD4(+)CD25(-)TGF-beta 1(+) adaptive Tregs. These cells were CD62L(low) and hypo-responsive to stimulation with cognate Ag but demonstrated a superior ability to suppress Ag-specific effector T cell response compared with their CD62L(high) counterparts. Importantly, treatment of mice with autoimmune thyroiditis using mouse thyroglobulin (mTg)-pulsed anti-CTLA-4 agonistic Ab-coated DCs, which results in a dominant engagement of CTLA-4 upon self-Ag presentation, not only suppressed thyroiditis but also prevented reemergence of the disease upon rechallenge with mTg. Further, the disease suppression was associated with significantly reduced mTg-specific T cell and Ab responses. Collectively, our results showed an important role for selective CTLA-4 signaling in the induction of adaptive Tregs and suggested that approaches that allow dominant CTLA-4 engagement concomitant with Ag-specific TCR ligation can be used for targeted therapy.