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Ablation of Transcription Factor IRF4 Promotes Transplant Acceptance by Driving Allogenic CD4+ T Cell Dysfunction.

Immunity (2017-12-10)
Jie Wu, Hedong Zhang, Xiaomin Shi, Xiang Xiao, Yihui Fan, Laurie J Minze, Jin Wang, Rafik M Ghobrial, Jiahong Xia, Roger Sciammas, Xian C Li, Wenhao Chen
RESUMEN

CD4+ T cells orchestrate immune responses and destruction of allogeneic organ transplants, but how this process is regulated on a transcriptional level remains unclear. Here, we demonstrated that interferon regulatory factor 4 (IRF4) was a key transcriptional determinant controlling T cell responses during transplantation. IRF4 deletion in mice resulted in progressive establishment of CD4+ T cell dysfunction and long-term allograft survival. Mechanistically, IRF4 repressed PD-1, Helios, and other molecules associated with T cell dysfunction. In the absence of IRF4, chromatin accessibility and binding of Helios at PD-1 cis-regulatory elements were increased, resulting in enhanced PD-1 expression and CD4+ T cell dysfunction. The dysfunctional state of Irf4-deficient T cells was initially reversible by PD-1 ligand blockade, but it progressively developed into an irreversible state. Hence, IRF4 controls a core regulatory circuit of CD4+ T cell dysfunction, and targeting IRF4 represents a potential therapeutic strategy for achieving transplant acceptance.

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Ionomycin calcium salt, Ready Made Solution, from Streptomyces conglobatus, 1 mM in DMSO
Sigma-Aldrich
ChIPAb+ Trimethyl-Histone H3 (Lys4) - ChIP Validated Antibody and Primer Set, clone CMA304, from mouse, purified by using protein G