Linsley P S, Greene J L, Tan P, Bradshaw J, Ledbetter J A, Anasetti C, Damle N K
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121.
J Exp Med. 1992 Dec 1;176(6):1595-604. doi: 10.1084/jem.176.6.1595.
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.
抗原呈递细胞（APC）上的分子对T细胞的共刺激是T细胞最佳增殖所必需的。APC上的B7分子与T淋巴细胞受体CD28结合，触发白细胞介素2（IL-2）产生增加及随后的T细胞增殖。CTLA-4是一种预测的与CD28同源的T细胞膜受体，它也与B7配体结合，但其分布和功能尚不清楚。在此，我们制备了针对CTLA-4的单克隆抗体（mAb）并研究了这些问题。所产生的mAb能结合CTLA-4而不结合CD28，并能阻断CTLA-4与B7的结合。用这些mAb检测发现，静止T细胞上几乎检测不到CTLA-4的表达，但在T细胞活化过程中其表达增加了数百倍。在活化的淋巴细胞上，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，最高达到CD28水平的约1/30 - 50。尽管其表达较低，但CTLA-4却负责大量活化T细胞与B7的结合。抗CTLA-4 mAb 11D4和抗CD28 mAb 9.3协同作用可抑制T细胞与B7的黏附，并阻断原代混合淋巴细胞培养中的T细胞增殖。当与抗T细胞受体（TCR）mAb共同固定时，抗CTLA-4 mAb在共刺激静止或活化T细胞增殖方面不如抗CD28 mAb 9.3有效。然而，抗CD28和抗CTLA-4的共同固定组合在增强抗TCR诱导的预活化CD4+T细胞增殖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介导的T细胞黏附和活化。
