Ding L, Shevach E M
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda 20892.
Eur J Immunol. 1994 Apr;24(4):859-66. doi: 10.1002/eji.1830240413.
Increasing evidence in both murine and human systems suggests that the interaction of the T cell surface antigens CD28/CTLA4 with their ligand B7 on the antigen-presenting cells (APC) is the critical costimulatory pathway involved in the induction of maximal T cell activation and the prevention of induction of anergy. It has also been demonstrated that efficient induction of clonal expansion of normal CD4+ T cells requires the delivery of the T cell receptor (TCR) ligand and costimulation by the same APC. We demonstrate here that normal murine CD4+ T cells can be efficiently activated by soluble anti-CD3 cross-linked by fixed macrophages and by a costimulatory signal delivered by a bystander APC, B7-transfected L cells. The major factor which determined the ability of an APC to provide costimulation in "trans" was the level of cell surface B7 expression. The requirement for B7 costimulation appears to be at initial stage of TCR engagement since optimal T cell activation was only observed when TCR triggering and B7 costimulatory activity were delivered at same time by different APC. Induction of maximal proliferation of both naive CD45RBhi and memory CD45RBlo CD4+ T cells was B7 dependent and both populations of cells responded equally well to the B7 costimulation delivered in "trans". Furthermore, trans-costimulation provided by B7 transfected L cells efficiently prevented the induction of anergy in normal murine CD4+ T cells induced by anti-CD3 cross-linked by fixed-resting macrophages. Addition of exogenous interleukin-2 (IL-2) and IL-7 to the primary culture in the absence of B7-transfected L cells or addition of IL-2 to the culture containing the B7 transfectant and CTLA4Ig completely prevented the induction of hyporesponsiveness. These findings raise the possibility that in certain pathological states, CD4+ T cells in vivo may be activated by costimulation delivered by bystander APC.
越来越多在小鼠和人类系统中的证据表明，T细胞表面抗原CD28/CTLA4与其在抗原呈递细胞（APC）上的配体B7之间的相互作用，是诱导T细胞最大程度激活以及防止无反应性诱导的关键共刺激途径。也已经证明，正常CD4⁺ T细胞克隆扩增的有效诱导需要T细胞受体（TCR）配体的传递以及来自同一APC的共刺激。我们在此证明，正常小鼠CD4⁺ T细胞可被固定巨噬细胞交联的可溶性抗CD3以及旁观者APC（B7转染的L细胞）传递的共刺激信号有效激活。决定APC在“反式”中提供共刺激能力的主要因素是细胞表面B7的表达水平。对B7共刺激的需求似乎在TCR结合的初始阶段，因为只有当TCR触发和B7共刺激活性由不同的APC同时传递时，才能观察到最佳的T细胞激活。幼稚CD45RBhi和记忆CD45RBlo CD4⁺ T细胞的最大增殖诱导均依赖于B7，并且这两种细胞群体对“反式”传递的B7共刺激反应同样良好。此外，B7转染的L细胞提供的反式共刺激有效地防止了由固定静止巨噬细胞交联的抗CD3诱导的正常小鼠CD4⁺ T细胞无反应性的诱导。在没有B7转染的L细胞的情况下向原代培养物中添加外源性白细胞介素-2（IL-2）和IL-7，或者向含有B7转染体和CTLA4Ig 的培养物中添加IL-2，都完全防止了低反应性的诱导。这些发现增加了一种可能性，即在某些病理状态下，体内的CD4⁺ T细胞可能被旁观者APC传递的共刺激激活。
