Damle N K, Klussman K, Linsley P S, Aruffo A
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121.
J Immunol. 1992 Apr 1;148(7):1985-92.
Optimal proliferation of T cells although initiated via ligation of the CD3/TCR complex requires additional stimulation resulting from adhesive interactions between costimulatory receptors (R) on T cells and their counter-R on APC. At least four distinct adhesion molecules (counter-R) present on APC, B7, ICAM-1 (CD54), LFA-3 (CD58), and VCAM-1 have been individually shown to costimulate T cell activation. Because some of these molecules may be expressed simultaneously on APC, it has been difficult to examine relative contributions of individual counter-R during the induction of T cell proliferation. We have produced soluble IgC gamma 1 fusion chimeras (receptor globulins or Rg) of B7, ICAM-1, LFA-3, and VCAM-1 and compared their relative abilities to costimulate proliferation of resting or Ag-primed CD4+ T cells. When co-immobilized with mAb directed at TCR alpha beta or CD3 but not CD2 or CD28, each Rg induced proliferation of both resting and Ag-primed CD4+ cells. In contrast, similarly co-immobilized CD7 Rg or ELAM-1 Rg were ineffective. Resting CD4+ T cells produced more IL-2, expressed significantly higher levels of IL-2R alpha, and proliferated more efficiently when costimulated with either ICAM-1 Rg or VCAM-1 Rg than with B7 Rg or LFA-3 Rg. CD4+ CD45RO+ memory T cells proliferated more vigorously in response to the costimulation by each of the four Rg than CD4+ CD45RA+ naive T cells. In contrast with the behavior of resting CD4+ T cells, proliferation of Ag-preactivated CD4+ T cells was most efficient when costimulated by B7 Rg. The costimulatory effect of LFA-3 Rg on Ag-primed CD4+ T cells was weaker than that of B7 Rg but was significantly greater than that of either ICAM-1 Rg or VCAM-1 Rg. These results suggest that resting and Ag-primed CD4+ T cells preferentially respond by proliferation to different costimulatory counter-R. ICAM-1 and VCAM-1 may be involved in the initiation of proliferation of Ag-responsive T cells, and B7 and LFA-3 may facilitate sustained proliferation of Ag-primed T cells. The cumulative costimulation by the above counter-R may facilitate optimal expression of various regulatory and effector functions of T cells.
T细胞的最佳增殖虽然通过CD3/TCR复合物的连接启动，但还需要共刺激受体（R）在T细胞上与其在抗原呈递细胞（APC）上的相应R之间的粘附相互作用产生的额外刺激。APC上存在的至少四种不同的粘附分子（相应R），即B7、细胞间粘附分子-1（ICAM-1，CD54）、淋巴细胞功能相关抗原-3（LFA-3，CD58）和血管细胞粘附分子-1（VCAM-1），已分别被证明可共刺激T细胞活化。由于这些分子中的一些可能在APC上同时表达，因此很难在T细胞增殖诱导过程中研究单个相应R的相对作用。我们制备了B7、ICAM-1、LFA-3和VCAM-1的可溶性IgCγ1融合嵌合体（受体球蛋白或Rg），并比较了它们共刺激静息或抗原致敏的CD4+T细胞增殖的相对能力。当与针对TCRαβ或CD3而非CD2或CD28的单克隆抗体共同固定时，每种Rg均可诱导静息和抗原致敏的CD4+细胞增殖。相比之下，类似地共同固定的CD7 Rg或ELAM-1 Rg则无效。与用B7 Rg或LFA-3 Rg共刺激相比，静息CD4+T细胞在用ICAM-1 Rg或VCAM-1 Rg共刺激时产生更多的白细胞介素-2（IL-2），IL-2受体α（IL-2Rα）表达水平显著更高，且增殖更有效。CD4+CD45RO+记忆T细胞对四种Rg中的每一种共刺激的反应均比CD4+CD45RA+初始T细胞更强烈。与静息CD4+T细胞的行为相反，抗原预激活的CD4+T细胞在用B7 Rg共刺激时增殖最有效。LFA-3 Rg对抗原致敏的CD4+T细胞的共刺激作用弱于B7 Rg，但明显强于ICAM-1 Rg或VCAM-1 Rg。这些结果表明，静息和抗原致敏的CD4+T细胞通过增殖优先对不同的共刺激相应R作出反应。ICAM-1和VCAM-1可能参与抗原反应性T细胞增殖的启动，而B7和LFA-3可能促进抗原致敏T细胞的持续增殖。上述相应R的累积共刺激可能促进T细胞各种调节和效应功能的最佳表达。
