Ablation of interferon regulatory factor 4 in T cells induces "memory" of transplant tolerance that is irreversible by immune checkpoint blockade
Ablation of interferon regulatory factor 4 in T cells induces "memory" of transplant tolerance that is irreversible by immune checkpoint blockade
复制标题
DOI：
10.1111/ajt.15196
复制
发表时间：
2019-03-01
影响因子：
8.8
通讯作者：
Chen, Wenhao
中科院分区：
文献类型：
--
作者：
Zhang, Hedong;Wu, Jie;Chen, Wenhao
实现移植耐受仍然是器官移植领域的最终目标。我们先前证明，T细胞中转录因子干扰素调节因子4（IRF 4）的消融通过驱动同种异体CD 4（+）T细胞功能障碍诱导心脏移植接受。在此，我们发现T细胞特异性IRF 4缺失的心脏移植小鼠对供体特异性抗原具有耐受性，并接受随后移植的供体类型，但不接受第三方皮肤同种异体移植物。此外，尽管在免疫检查点阻断下T细胞特异性Irf 4敲除小鼠中的原代心脏移植物发生排斥，但在这些小鼠中建立供体特异性耐受性不受阻碍。通过在体内追踪同种异体抗原特异性CD 4（+）T细胞，我们发现，在心脏移植后第6天，检查点阻断恢复了Irf 4缺陷型T细胞中大多数野生型T细胞表达基因的表达水平，表明Irf 4缺陷型T细胞的初始复苏。然而，在心脏移植后第30天，检查点阻断并没有恢复Irf 4（-/-）同种异体反应性T细胞的细胞频率、效应记忆细胞产生和IFN-γ/TNF-α产生。因此，靶向IRF 4代表了驱动内在T细胞功能障碍和实现同种异体抗原特异性移植耐受的潜在治疗策略。
Achieving transplant tolerance remains the ultimate goal in the field of organ transplantation. We demonstrated previously that ablation of the transcription factor interferon regulatory factor 4 (IRF4) in T cells induced heart transplant acceptance by driving allogeneic CD4(+) T cell dysfunction. Herein, we showed that heart-transplanted mice with T cell-specific IRF4 deletion were tolerant to donor-specific antigens and accepted the subsequently transplanted donor-type but not third-party skin allografts. Moreover, despite the rejection of the primary heart grafts in T cell-specific Irf4 knockout mice under immune checkpoint blockade, the establishment of donor-specific tolerance in these mice was unhindered. By tracking alloantigen-specific CD4(+) T cells in vivo, we revealed that checkpoint blockade restored the expression levels of the majority of wild-type T cell-expressed genes in Irf4-deficient T cells on day 6 post-heart grafting, indicating the initial reinvigoration of Irf4-deficient T cells. Nevertheless, checkpoint blockade did not restore cell frequency, effector memory cell generation, and IFN-gamma/TNF-alpha production of Irf4(-/-) alloreactive T cells at day 30 post-heart grafting. Hence, targeting IRF4 represents a potential therapeutic strategy for driving intrinsic T cell dysfunction and achieving alloantigen-specific transplant tolerance.