Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes.
Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes.
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DOI：
10.1084/jem.176.6.1595
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发表时间：
1992-12-01
期刊：
影响因子：
--
通讯作者：
Damle NK
中科院分区：
文献类型：
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作者：
Linsley PS;Greene JL;Tan P;Bradshaw J;Ledbetter JA;Anasetti C;Damle NK
抗原呈递细胞（APC）上的分子对T细胞的共刺激是T细胞增殖的最佳条件。APC上的B7分子与T淋巴细胞受体CD28结合，引发白细胞介素2 （IL-2）的产生增加和随后的T细胞增殖。CTLA-4是一种预测的T细胞膜受体，与CD28同源，也能结合B7对抗受体，但其分布和功能尚不清楚。在这里，我们开发了针对CTLA-4的单克隆抗体（mab），并对这些问题进行了研究。制备的单克隆抗体能结合CTLA-4而不结合CD28，阻断CTLA-4与B7的结合。通过这些单克隆抗体测量的CTLA-4表达在静止T细胞上几乎检测不到，但在T细胞激活期间增加了数百倍。在活化淋巴细胞上，CTLA-4在CD4+和CD8+ T细胞亚群上表达相同，并与CD25、CD28和CD45RO共表达。CTLA-4的表达低于CD28，最高约为CD28的1/30-50。尽管CTLA-4的表达水平较低，但它在很大程度上负责B7与大型活化T细胞的结合。在原代混合淋巴细胞培养中，Anti-CTLA-4 mAb 11D4和anti-CD28 mAb 9.3协同抑制T细胞对B7的粘附，阻断T细胞增殖。当与抗T细胞受体（TCR）单抗共固定时，抗ctla -4单抗在共刺激静止或活化T细胞增殖方面的效果低于抗cd28单抗9.3。然而，抗cd28和抗ctla -4的共固定组合在增强抗tcr诱导的预激活CD4+ T细胞增殖的能力方面具有协同作用。这些结果表明CTLA-4与CD28在活化的T淋巴细胞上共表达，并协同调节B7对T细胞的粘附和活化。
T cell costimulation by molecules on the antigen presenting cell (APC) is required for optimal T cell proliferation. The B7 molecule on APC binds the T lymphocyte receptor CD28, triggering increased interleukin 2 (IL-2) production and subsequent T cell proliferation. CTLA-4 is a predicted T cell membrane receptor homologous to CD28, which also binds the B7 counter receptor, but whose distribution and function are unknown. Here we have developed monoclonal antibodies (mAbs) specific for CTLA-4 and have investigated these questions. mAbs were produced that bound CTLA-4 but not CD28, and that blocked binding of CTLA-4 to B7. CTLA-4 expression as measured by these mAbs was virtually undetectable on resting T cells, but was increased several hundred-fold during T cell activation. On activated lymphocytes, CTLA-4 was expressed equally on CD4+ and CD8+ T cell subsets and was coexpressed with CD25, CD28, and CD45RO. CTLA-4 expression was lower than that of CD28, reaching a maximum of approximately 1/30-50 the level of CD28. Despite its lower expression, CTLA-4 was responsible for much of the B7 binding by large activated T cells. Anti-CTLA-4 mAb 11D4 and anti-CD28 mAb 9.3 acted cooperatively to inhibit T cell adhesion to B7, and to block T cell proliferation in primary mixed lymphocyte culture. When coimmobilized with anti T cell receptor (TCR) mAb, anti-CTLA-4 mAbs were less effective than anti-CD28 mAb 9.3 at costimulating proliferation of resting or activated T cells. However, coimmobilized combinations of anti-CD28 and anti-CTLA-4 were synergistic in their ability to augment anti-TCR-induced proliferation of preactivated CD4+ T cells. These results indicate that CTLA-4 is coexpressed with CD28 on activated T lymphocytes and cooperatively regulates T cell adhesion and activation by B7.