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Ablation of interferon regulatory factor 4 in T cells induces “memory” of transplant tolerance that is irreversible by immune checkpoint blockade
Author(s) -
Zhang Hedong,
Wu Jie,
Zou Dawei,
Xiao Xiang,
Yan Hui,
Li Xian C.,
Chen Wenhao
Publication year - 2019
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.15196
Subject(s) - immune checkpoint , blockade , cancer research , medicine , irf4 , t cell , immunology , interferon regulatory factors , immune system , transplantation , transplant rejection , immune tolerance , transcription factor , immunotherapy , biology , microbiology and biotechnology , receptor , innate immune system , biochemistry , gene
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 ( IRF 4) in T cells induced heart transplant acceptance by driving allogeneic CD 4 + T cell dysfunction. Herein, we showed that heart‐transplanted mice with T cell‐specific IRF 4 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 CD 4 + 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 IRF 4 represents a potential therapeutic strategy for driving intrinsic T cell dysfunction and achieving alloantigen‐specific transplant tolerance.