Dubey C, Croft M, Swain S L
Department of Biology, University of California, at San Diego, La Jolla 92093, USA.
J Immunol. 1995 Jul 1;155(1):45-57.
Efficient initiation of a CD4 T cell response requires both activation through the TCR and costimulation provided by molecules on APC with counterreceptors on the T cell. We investigated the relative contribution of the ICAM-1:LFA-1 and B7:CD28/CTLA-4 costimulatory pathways in naive T cell activation, using either anti-CD28 Ab or fibroblast cell lines transfected with I-Ek, which express either no costimulatory molecules, ICAM-1 alone, B7-1 alone, or ICAM-1 and B7-1 together. Peptide Ag or immobilized anti-CD3 was used to provide the TCR signal. CD4 T cells from mice transgenic for the V beta 3/V alpha 11 TCR, which recognize a peptide of pigeon cytochrome c complexed to I-Ek, were used as a source of naive T cells. Naive T cells stimulated with Ag or anti-CD3 responded well to high numbers of APC expressing either ICAM-1 alone or B7-1 alone. However, APC expressing both ICAM-1 and B7-1 were much better stimulators of proliferation and IL-2 secretion at low cell numbers, and were far superior inducers of IL-2 at higher numbers, indicating a synergy between the two pathways. Stimulation provided by ICAM-1 could not be solely attributed to adhesive strengthening of other pathways, since costimulation was seen when immobilized anti-CD3 was used and when ICAM-1 only APC were added, indicating that ICAM-1 was in fact acting as a classic costimulatory molecule. Both the magnitude of the response and the amount of costimulation required for response were dependent on the intensity of TCR interaction. These results suggest that an efficient naive T cell response requires both a strong TCR signal and more than one costimulatory signal that will synergize with the TCR signal. This offers an explanation as to why APC such as dendritic cells and activated B cells, which express high levels of multiple costimulatory/adhesion molecules, are the only APC that elicit naive T cell responses.
CD4 T细胞反应的有效启动既需要通过TCR的激活，也需要抗原呈递细胞（APC）上的分子与T细胞上的共受体提供的共刺激。我们使用抗CD28抗体或转染了I-Ek的成纤维细胞系，研究了ICAM-1:LFA-1和B7:CD28/CTLA-4共刺激途径在初始T细胞激活中的相对作用，这些细胞系分别不表达共刺激分子、仅表达ICAM-1、仅表达B7-1或同时表达ICAM-1和B7-1。肽抗原或固定化抗CD3用于提供TCR信号。来自Vβ3/Vα11 TCR转基因小鼠的CD4 T细胞，其识别与I-Ek复合的鸽细胞色素c肽，用作初始T细胞来源。用抗原或抗CD3刺激的初始T细胞对大量仅表达ICAM-1或仅表达B7-1的APC反应良好。然而，同时表达ICAM-1和B7-1的APC在低细胞数量时是更好的增殖和IL-2分泌刺激剂，在高细胞数量时是更优越的IL-2诱导剂，表明两条途径之间存在协同作用。ICAM-1提供的刺激不能仅仅归因于其他途径的黏附增强，因为当使用固定化抗CD3时以及当仅添加ICAM-1的APC时都观察到了共刺激，这表明ICAM-1实际上起着经典共刺激分子的作用。反应的幅度和反应所需的共刺激量都取决于TCR相互作用的强度。这些结果表明，有效的初始T细胞反应既需要强烈的TCR信号，也需要不止一个与TCR信号协同作用的共刺激信号。这解释了为什么诸如树突状细胞和活化B细胞等表达高水平多种共刺激/黏附分子的APC是唯一能引发初始T细胞反应的APC。
