Ablation of interferon regulatory factor 4 in T cells induces “memory” of transplant tolerance that is irreversible by immune checkpoint blockade

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-γ/TNF-α 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.