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

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

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

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. 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.

Original languageEnglish (US)
JournalImmunity
Early online dateDec 4 2017
DOIs
StateE-pub ahead of print - Dec 4 2017

Keywords

  • Interferon regulatory factor 4
  • Programmed cell death protein 1
  • T cell dysfunction
  • Transcriptional regulation
  • Transplant acceptance

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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