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

Publication date: Available online 5 December 2017
Source:Immunity
Author(s): 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
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.

Graphical abstract

Teaser

CD4⁺ T cells drive allogeneic organ transplant destruction, but how this is regulated transcriptionally remains unclear. Wu et al. report that IRF4 deletion in T cells leads to the establishment of T cell dysfunction and long-term allograft survival. Therefore, targeting IRF4 represents a therapeutic opportunity for achieving transplant acceptance.


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