Engagement of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) induces transforming growth factor beta (TGF-beta) production by murine CD4(+) T cells.
Engagement of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) induces transforming growth factor beta (TGF-beta) production by murine CD4(+) T cells.
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DOI：
10.1084/jem.188.10.1849
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发表时间：
1998-11-16
期刊：
影响因子：
--
通讯作者：
Wahl SM
中科院分区：
文献类型：
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作者：
Chen W;Jin W;Wahl SM
有证据表明，细胞毒性T淋巴细胞相关抗原4（CTLA-4）可以负调节T细胞活化，但抑制作用的基础仍然未知。我们在此报道CTLA-4的交联诱导小鼠CD 4 + T细胞产生转化生长因子β（TGF-β）。在CTLA-4的抗体交联后，CD 4 + 1型辅助性T细胞（Th 1）、Th 2和Th 0克隆均分泌TGF-β，表明CTLA-4信号传导诱导TGF-β代表鼠CD 4 + T细胞的普遍特征。CD 3-T细胞抗原受体复合物的刺激并不独立地诱导TGF-β，而是最佳CTLA-4介导的TGF-β产生所需的。CTLA-4与CD 3和CD 28交联的结果包括抑制T细胞增殖和白细胞介素（IL）-2分泌，以及抑制干扰素γ（Th 1）和IL-4（Th 2）。此外，添加抗TGF-β部分逆转了这种T细胞抑制。当CTLA-4在TGF-β1基因缺失（TGF-β1−/−）小鼠的T细胞群中交联时，T细胞反应仅被抑制38%，而野生型小鼠中为95%。我们的数据表明，CTLA-4的参与导致CD 4 + T细胞产生TGF-β，这在一定程度上有助于T细胞活化的下调。CTLA-4，通过TGF-β，可以作为一个平衡的CD 28共刺激IL-2和CD 4 + T细胞活化。
Evidence indicates that cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) may negatively regulate T cell activation, but the basis for the inhibitory effect remains unknown. We report here that cross-linking of CTLA-4 induces transforming growth factor β (TGF-β) production by murine CD4+ T cells. CD4+ T helper type 1 (Th1), Th2, and Th0 clones all secrete TGF-β after antibody cross-linking of CTLA-4, indicating that induction of TGF-β by CTLA-4 signaling represents a ubiquitous feature of murine CD4+ T cells. Stimulation of the CD3–T cell antigen receptor complex does not independently induce TGF-β, but is required for optimal CTLA-4–mediated TGF-β production. The consequences of cross-linking of CTLA-4, together with CD3 and CD28, include inhibition of T cell proliferation and interleukin (IL)-2 secretion, as well as suppression of both interferon γ (Th1) and IL-4 (Th2). Moreover, addition of anti–TGF-β partially reverses this T cell suppression. When CTLA-4 was cross-linked in T cell populations from TGF-β1 gene–deleted (TGF-β1−/−) mice, the T cell responses were only suppressed 38% compared with 95% in wild-type mice. Our data demonstrate that engagement of CTLA-4 leads to CD4+ T cell production of TGF-β, which, in part, contributes to the downregulation of T cell activation. CTLA-4, through TGF-β, may serve as a counterbalance for CD28 costimulation of IL-2 and CD4+ T cell activation.