Vandenborre K, Van Gool S W, Kasran A, Ceuppens J L, Boogaerts M A, Vandenberghe P
Laboratory for Experimental Hematology, University of Leuven, Belgium.
Immunology. 1999 Nov;98(3):413-21. doi: 10.1046/j.1365-2567.1999.00888.x.
Occupancy of CTLA-4 (cytotoxic T-lymphocyte antigen-4 or CD152) negatively regulates the activation of mouse T lymphocytes, as indicated by the fate of CTLA-4-deficient mice, by the impact of anti-CTLA-4 monoclonal antibodies (mAbs) on mouse T-cell activation in vitro and by the impact of CTLA-4 blockade on the course of experimental tumoral, autoimmune, alloimmune or infectious disease in this animal. The function of human CTLA-4, however, remains less clear. The expression and function of human CTLA-4 were further explored. CTLA-4 was expressed under mitogenic conditions only, its expression being, at least partially, dependent on the secretion of interleukin-2. Memory T cells expressed CTLA-4 with faster kinetics than naive T cells. The functional role of human CTLA-4 was assessed utilizing a panel of four anti-CTLA-4 mAbs that blocked the interaction between CTLA-4 and its ligands. These mAbs, in immobilized form, profoundly inhibited the activation of T cells by immobilized anti-CD3 mAb in the absence of anti-CD28 mAb, but co-stimulated T-cell activation in the presence of anti-CD28 mAb. Finally, and importantly, blockade of the interaction of CTLA-4 with its ligands using soluble anti-CTLA-4 mAbs, in intact form or as Fab fragments, enhanced T-cell activation in several polyclonal or alloantigen-specific CD80- or CD80/CD86-dependent assays, as measured by cytokine production, cellular proliferation or cytotoxic responses. It is concluded that interaction of CTLA-4 with its functional ligands, CD80 or CD86, can down-regulate human T-cell responses, probably by intracellular signalling events and independent of CD28 occupancy.
细胞毒性T淋巴细胞相关抗原4（CTLA-4，又称CD152）的占据会对小鼠T淋巴细胞的激活产生负调节作用，这一点可通过CTLA-4缺陷小鼠的命运、抗CTLA-4单克隆抗体（mAb）对体外小鼠T细胞激活的影响以及CTLA-4阻断对该动物实验性肿瘤、自身免疫、同种免疫或感染性疾病进程的影响得以证明。然而，人类CTLA-4的功能仍不太明确。对人类CTLA-4的表达和功能进行了进一步探索。CTLA-4仅在促有丝分裂条件下表达，其表达至少部分依赖于白细胞介素-2的分泌。记忆性T细胞比初始T细胞以更快的动力学表达CTLA-4。利用一组四种抗CTLA-4 mAb评估了人类CTLA-4的功能作用，这些mAb可阻断CTLA-4与其配体之间的相互作用。这些固定形式的mAb在不存在抗CD28 mAb的情况下，能显著抑制固定化抗CD3 mAb对T细胞的激活，但在存在抗CD28 mAb时会共刺激T细胞激活。最后且重要的是，使用完整形式或Fab片段的可溶性抗CTLA-4 mAb阻断CTLA-4与其配体的相互作用，在几种多克隆或同种异体抗原特异性的依赖CD80或CD80/CD86的检测中，通过细胞因子产生、细胞增殖或细胞毒性反应测量，增强了T细胞激活。得出的结论是，CTLA-4与其功能性配体CD80或CD86的相互作用可能通过细胞内信号事件下调人类T细胞反应，且独立于CD28的占据情况。
