Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, Georgia.
Am J Transplant. 2020 Aug;20(8):2206-2215. doi: 10.1111/ajt.15837. Epub 2020 Mar 24.
Donor-reactive memory T cells generated via heterologous immunity represent a potent barrier to long-term graft survival following transplantation because of their increased precursor frequency, rapid effector function, altered trafficking patterns, and reduced reliance on costimulation signals for activation. Thus, the identification of pathways that control memory T cell survival and secondary recall potential may provide new opportunities for therapeutic intervention. Here, we discovered that donor-specific effector/memory CD8 T cell populations generated via exposure to acute vs latent vs chronic infections contain differential frequencies of CD8 T cells expressing the inhibitory Fc receptor FcγRIIB. Results indicated that frequencies of FcγRIIB-expressing CD8 donor-reactive memory T cells inversely correlated with allograft rejection. Furthermore, adoptive T cell transfer of Fcgr2b CD8 T cells resulted in an accumulation of donor-specific CD8 memory T cells and enhanced recall responses, indicating that FcγRIIB functions intrinsically to limit T cell CD8 survival in vivo. Lastly, we show that deletion of FcγRIIB on donor-specific CD8 memory T cells precipitated costimulation blockade-resistant rejection. These data therefore identify a novel cell-intrinsic inhibitory pathway that functions to limit the risk of memory T cell-mediated rejection following transplantation and suggest that therapeutic manipulation of this pathway could improve outcomes in sensitized patients.
通过异源免疫产生的供体反应性记忆 T 细胞由于其较高的前体频率、快速的效应功能、改变的迁移模式以及对激活的共刺激信号的依赖减少，代表了移植后长期移植物存活的一个强大障碍。因此，鉴定控制记忆 T 细胞存活和二次召回潜能的途径可能为治疗干预提供新的机会。在这里，我们发现通过暴露于急性、潜伏性和慢性感染而产生的供体特异性效应/记忆 CD8 T 细胞群体中表达抑制性 Fc 受体 FcγRIIB 的 CD8 T 细胞的频率存在差异。结果表明，表达 FcγRIIB 的 CD8 供体反应性记忆 T 细胞的频率与同种异体移植物排斥呈负相关。此外，Fcgr2b CD8 T 细胞的过继性 T 细胞转移导致供体特异性 CD8 记忆 T 细胞的积累和增强的回忆反应，表明 FcγRIIB 内在地作用于限制体内 T 细胞 CD8 的存活。最后，我们表明在供体特异性 CD8 记忆 T 细胞上缺失 FcγRIIB 会引发协同刺激阻断耐药性排斥。因此，这些数据确定了一种新的细胞内在抑制途径，该途径可限制移植后记忆 T 细胞介导的排斥反应的风险，并表明对该途径的治疗性操作可能改善致敏患者的预后。
