A transendocytosis model of CTLA-4 function predicts its suppressive behavior on regulatory T cells.
A transendocytosis model of CTLA-4 function predicts its suppressive behavior on regulatory T cells.
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DOI：
10.4049/jimmunol.1401876
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发表时间：
2015-03-01
期刊：
影响因子：
--
通讯作者：
Sansom DM
中科院分区：
文献类型：
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作者：
Hou TZ;Qureshi OS;Wang CJ;Baker J;Young SP;Walker LS;Sansom DM
CD 28/CTLA-4通路的操纵是在自身免疫和癌症中使用的许多免疫调节方法的核心。虽然很明显CTLA-4是T细胞应答的关键调节剂，但CTLA-4控制免疫应答的免疫学背景尚未明确。在这里，我们表明，虽然CD 80/CD 86依赖性活化的静息人T细胞引起广泛的T细胞增殖和强大的CTLA-4表达，在这种情况下，CTLA-4阻断抗体对反应没有影响。相比之下，在CTLA-4+细胞作为“调节剂”存在的情况下，静息T细胞应答的抑制依赖于CTLA-4表达，并且与抗原呈递细胞的数量特别相关。在低数量的APC或低水平的配体下，CTLA-4依赖性抑制是高度有效的，而在较高的APC数量或高水平的配体下，抑制丧失。因此，抑制程度与抗原呈递细胞上残留的CD 86表达水平相关。这些数据揭示了CTLA-4对Treg的抑制功能的明确规则，这是通过其从抗原呈递细胞中去除配体的能力来预测的。
Manipulation of the CD28/CTLA-4 pathway is at the heart of a number of immunomodulatory approaches used in both autoimmunity and cancer. Whilst it is clear that CTLA-4 is a critical regulator of T cell responses, the immunological contexts in which CTLA-4 controls immune responses are not well defined. Here we show that whilst CD80/CD86-dependent activation of resting human T cells caused extensive T cell proliferation and robust CTLA-4 expression, in this context CTLA-4 blocking antibodies had no impact on the response. In contrast, in settings where CTLA-4+ cells were present as “regulators”, inhibition of resting T cell responses was dependent on CTLA-4 expression and specifically related to the number of antigen presenting cells. At low numbers of APC or low levels of ligand, CTLA-4-dependent suppression was highly effective whereas at higher APC numbers or high levels of ligand, inhibition was lost. Accordingly, the degree of suppression correlated with the level of CD86 expression remaining on the antigen presenting cells. These data reveal clear rules for the inhibitory function of CTLA-4 on Treg which are predicted by its ability to remove ligands from antigen presenting cells.