Zhai Yuan, Wang Yue, Wu Zheng, Kupiec-Weglinski Jerzy W
Division of Liver and Pancreas Transplantation, Department of Surgery, Dumont-University of California Los Angeles Transplant Center, Los Angeles, CA 90095, USA.
J Immunol. 2007 Oct 1;179(7):4529-34. doi: 10.4049/jimmunol.179.7.4529.
We have shown that alloreactive CD8 T cell activation may proceed via CD4-dependent and CD4-independent pathways, and that CD8 T cell activation in Ag-primed animals is independent of CD154 costimulation. In this report, we further analyzed the activation and function of alloreactive CD8 CTL effectors in CD4 knockout (KO) skin/cardiac allograft recipients. FACS analysis showed that alloreactive CD8 T cells were activated at a significantly reduced level in CD4 KO mice. Importantly, these helpless CD8 T cells failed to develop CD154 blockade resistance following reactivation by the same alloantigen, indicative of defective memory formation. Only transient CD4 help was required, as short-term CD4 blockade at the time of first skin graft challenge only delayed alloreactive CD8 activation, without affecting the CD8 T cell memory response to a second skin graft. Moreover, postoperative CD4 blockade had no effect on alloreactive CD8 activation. Alloreactive CD8 cells generated in the absence of CD4 help exhibited decreased effector responses. Interestingly, intragraft induction of T cell-targeted chemokines early after transplant was also dependent on CD4 help, as the induction kinetics of CXCL9 and CCL5 in CD4 KO recipients was significantly delayed, coupled with similarly delayed infiltration by CD3/CD8 cells. Remarkably, helpless CD8 cells ultimately entering the graft still displayed significantly diminished T cell effector molecules (IFN-gamma, granzyme B). Thus, CD4 help is critical for alloreactive CD8 activation, function, and memory formation.
我们已经表明，同种异体反应性CD8 T细胞的激活可能通过CD4依赖和CD4非依赖途径进行，并且在抗原致敏动物中CD8 T细胞的激活不依赖于CD154共刺激。在本报告中，我们进一步分析了同种异体反应性CD8 CTL效应细胞在CD4基因敲除（KO）皮肤/心脏同种异体移植受者中的激活和功能。流式细胞术分析表明，在CD4 KO小鼠中，同种异体反应性CD8 T细胞的激活水平显著降低。重要的是，这些无助的CD8 T细胞在被相同同种异体抗原再次激活后未能产生对CD154阻断的抗性，这表明记忆形成存在缺陷。只需要短暂的CD4辅助，因为在首次皮肤移植攻击时短期阻断CD4只会延迟同种异体反应性CD8的激活，而不会影响CD8 T细胞对第二次皮肤移植的记忆反应。此外，术后阻断CD4对同种异体反应性CD8的激活没有影响。在没有CD4辅助的情况下产生的同种异体反应性CD8细胞表现出效应反应降低。有趣的是，移植后早期移植物内T细胞靶向趋化因子的诱导也依赖于CD4辅助，因为CD4 KO受者中CXCL9和CCL5的诱导动力学显著延迟，同时CD3/CD8细胞的浸润也同样延迟。值得注意的是，最终进入移植物的无助CD8细胞仍然显示出T细胞效应分子（IFN-γ、颗粒酶B）显著减少。因此，CD4辅助对于同种异体反应性CD8的激活、功能和记忆形成至关重要。
