Analysis of the role of negative T cell costimulatory pathways in CD4 and CD8 T cell-mediated alloimmune responses in vivo
Analysis of the role of negative T cell costimulatory pathways in CD4 and CD8 T cell-mediated alloimmune responses in vivo
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DOI：
10.4049/jimmunol.174.11.6648
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发表时间：
2005-06-01
影响因子：
4.4
通讯作者：
Najafian, N
中科院分区：
文献类型：
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作者：
Ito, T;Ueno, T;Najafian, N
通过细胞表面分子如CTLA-4和程序性死亡1 （PD-1）介导的负共刺激信号在下调免疫应答和维持外周耐受中发挥关键作用。然而，它们在同种免疫反应中的作用尚不清楚。本研究考察了这些抑制途径在体内调节cd28依赖性和cd28非依赖性CD4和CD8同种异体反应性T细胞中的作用。CTLA-4阻断加速了C57BL/6野生型受者的移植排斥反应，并在一定比例的CD4（-/-）而CD8（-/-）受者中加速了BALB/c心脏的移植排斥反应。同样的处理导致CD28（-/-）和更小比例的CD4(-/-)CD28（-/-）小鼠的迅速排斥，而在CD8(-/-)CD28（-/-）受体中没有影响。这些结果表明，CTLA-4:B7通路为同种异体反应性CD8(+) T细胞提供了一个负信号，特别是在CD28共刺激的情况下。相比之下，PD-1阻断仅在CD28-/-和CD8(-/-)CD28（-/-）受体中导致同种异体心脏移植排斥反应加速。有趣的是，PD-1配体（PD-L1）阻断导致野生型小鼠和所有缺乏CD28共刺激的受体加速排斥。这种作用伴随着产生ifn - γ的同种异体反应性T细胞的扩增和排斥同种异体移植受体中效应T细胞的增强。因此，PD-1:PD-L1通路下调同种异体反应性CD4 T细胞，特别是在缺乏CD28共刺激的情况下。PD-1与PD-L1阻断的差异效应支持可能存在PD-1以外的通过PD-L1进行负信号传导的新受体。此外，PD-1:PD-L1通路可以独立于完整的CD28/CTLA-4:B7通路调节同种免疫应答。利用调节同种异体免疫的生理机制应该导致开发新的策略来诱导持久和可重复的移植耐受。
Negative costimulatory signals mediated via cell surface molecules such as CTLA-4 and programmed death 1 (PD-1) play a critical role in down-modulating immune responses and maintaining peripheral tolerance. However, their role in alloimmune responses remains unclear. This study examined the role of these inhibitory pathways in regulating CD28-dependent and CD28-independent CD4 and CD8 alloreactive T cells in vivo. CTLA-4 blockade accelerated graft rejection in C57BL/6 wild-type recipients and in a proportion of CD4(-/-) but not CD8(-/-) recipients of BALB/c hearts. The same treatment led to prompt rejection in CD28(-/-) and a smaller proportion of CD4(-/-)CD28(-/-) mice with no effect in CD8(-/-)CD28(-/-) recipients. These results indicate that the CTLA-4:B7 pathway provides a negative signal to alloreactive CD8(+) T cells, particularly in the presence of CD28 costimulation. In contrast, PD-1 blockade led to accelerated rejection of heart allografts only in CD28-/- and CD8(-/-)CD28(-/-) recipients. Interestingly, PD-1 ligand (PD-L1) blockade led to accelerated rejection in wild-type mice and in all recipients lacking CD28 costimulation. This effect was accompanied by expansion of IFN-gamma-producing alloreactive T cells and enhanced generation of effector T cells in rejecting allograft recipients. Thus, the PD-1:PD-L1 pathway down-regulates alloreactive CD4 T cells, particularly in the absence of CD28 costimulation. The differential effects of PD-1 vs PD-L1 blockade support the possible existence of a new receptor other than PD-1 for negative signaling through PD-L1. Furthermore, PD-1:PD-L1 pathway can regulate alloimmune responses independent of an intact CD28/CTLA-4:B7 pathway. Harnessing physiological mechanisms that regulate alloimmunity should lead to development of novel strategies to induce durable and reproducible transplantation tolerance.