Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
J Immunol. 2010 Apr 1;184(7):3450-60. doi: 10.4049/jimmunol.0903831. Epub 2010 Mar 1.
Donor Ag-reactive CD4 and CD8 T cell production of IFN-gamma is a principal effector mechanism promoting tissue injury during allograft rejection. The CXCR3-binding chemokines CXCL9 and CXCL10 recruit donor-reactive T cells to the allograft, but their role during the priming of donor-reactive T cells to effector function is unknown. Using a murine model of MHC-mismatched cardiac transplantation, we investigated the influence of CXCL9 and CXCL10 during donor-reactive T cell priming. In allograft recipient spleens, CXCL9 and CXCL10 were expressed as early as 24 h posttransplant and increased with similar kinetics, concurrently with CXCR3 expression on T cells. CXCL9, but not CXCL10, expression required NK cell production of IFN-gamma. The absence of CXCL9 in donor allografts, recipients, or both significantly decreased the frequency of donor-reactive CD8 T cells producing IFN-gamma and increased the frequency of donor-reactive CD8 T cells producing IL-17A. In contrast, the absence of CXCL10 increased the frequency of IFN-gamma-producing CD8 T cells in a CXCL9-dependent manner. These data provide novel evidence that donor-reactive CD8 T cells use the CXCR3 chemokine axis as a costimulation pathway during priming to allografts where CXCL9 promotes the development of IFN-gamma-producing CD8 T cells, and CXCL10 antagonizes this skewing.
供体 Ag 反应性 CD4 和 CD8 T 细胞产生 IFN-γ是促进同种异体移植物排斥反应中组织损伤的主要效应机制。CXCR3 结合趋化因子 CXCL9 和 CXCL10 将供体反应性 T 细胞募集到同种异体移植物中，但它们在供体反应性 T 细胞向效应功能的初始阶段的作用尚不清楚。使用 MHC 错配性心脏移植的小鼠模型，我们研究了 CXCL9 和 CXCL10 在供体反应性 T 细胞初始阶段的影响。在同种异体移植物受体脾脏中，CXCL9 和 CXCL10 的表达早在移植后 24 小时就出现，并以相似的动力学增加，同时伴有 T 细胞上的 CXCR3 表达。CXCL9 的表达，而不是 CXCL10 的表达，需要 NK 细胞产生 IFN-γ。供体同种异体移植物、受者或两者中 CXCL9 的缺失显著降低了产生 IFN-γ的供体反应性 CD8 T 细胞的频率，并增加了产生 IL-17A 的供体反应性 CD8 T 细胞的频率。相比之下，CXCL10 的缺失以 CXCL9 依赖的方式增加了产生 IFN-γ的 CD8 T 细胞的频率。这些数据提供了新的证据，表明供体反应性 CD8 T 细胞在同种异体移植物初始阶段使用 CXCR3 趋化因子轴作为共刺激途径，其中 CXCL9 促进 IFN-γ产生的 CD8 T 细胞的发育，而 CXCL10 拮抗这种偏向。
