Vu Minh Diem, Clarkson Michael R, Yagita Hideo, Turka Laurence A, Sayegh Mohamed H, Li Xian Chang
Transplant Research Center, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
J Immunol. 2006 Feb 1;176(3):1394-401. doi: 10.4049/jimmunol.176.3.1394.
Memory T cells can be a significant barrier to the induction of transplant tolerance. However, the molecular pathways that can regulate memory T cell-mediated rejection are poorly defined. In the present study we tested the hypothesis that the novel alternative costimulatory molecules (i.e., ICOS, 4-1BB, OX40, or CD30) may play a critical role in memory T cell activation and memory T cell-mediated rejection. We found that memory T cells, generated by either homeostatic proliferation or donor Ag priming, induced prompt skin allograft rejection regardless of CD28/CD154 blockade. Phenotypic analysis showed that, in contrast to naive T cells, such memory T cells expressed high levels of OX40, 4-1BB, and ICOS on the cell surface. In a skin transplant model in which rejection was mediated by memory T cells, blocking the OX40/OX40 ligand pathway alone did not prolong the skin allograft survival, but blocking OX40 costimulation in combination with CD28/CD154 blockade induced long-term skin allograft survival, and 40% of the recipients accepted their skin allograft for >100 days. In contrast, blocking the ICOS/ICOS ligand and the 4-1BB/4-1BBL pathways alone or combined with CD28/CD154 blockade had no effect in preventing skin allograft rejection. OX40 blockade did not affect the homeostatic proliferation of T cells in vivo, but markedly inhibited the effector functions of memory T cells. Our data demonstrate that memory T cells resisting to CD28/CD154 blockade in transplant rejection are sensitive to OX40 blockade and suggest that OX40 is a key therapeutic target in memory T cell-mediated rejection.
记忆性T细胞可能是诱导移植耐受的一个重要障碍。然而，调控记忆性T细胞介导的排斥反应的分子途径仍不清楚。在本研究中，我们检验了这样一个假设，即新型共刺激分子（即ICOS、4-1BB、OX40或CD30）可能在记忆性T细胞活化及记忆性T细胞介导的排斥反应中起关键作用。我们发现，无论是通过稳态增殖还是供体抗原激发产生的记忆性T细胞，均可诱导皮肤同种异体移植迅速排斥，而不受CD28/CD154阻断的影响。表型分析显示，与初始T细胞不同，此类记忆性T细胞在细胞表面高水平表达OX40、4-1BB和ICOS。在一个由记忆性T细胞介导排斥反应的皮肤移植模型中，单独阻断OX40/OX40配体途径并不能延长皮肤同种异体移植的存活时间，但联合阻断OX40共刺激与CD28/CD154可诱导皮肤同种异体移植长期存活，且40%的受者接受其皮肤同种异体移植超过100天。相比之下，单独阻断ICOS/ICOS配体和4-1BB/4-1BBL途径或联合CD28/CD154阻断在预防皮肤同种异体移植排斥方面均无效果。阻断OX40并不影响体内T细胞的稳态增殖，但显著抑制记忆性T细胞的效应功能。我们的数据表明，在移植排斥中抵抗CD28/CD154阻断的记忆性T细胞对OX40阻断敏感，并提示OX40是记忆性T细胞介导的排斥反应中的关键治疗靶点。
