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

8 Citations (Scopus)

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
DOIs
StateAccepted/In press - Jan 1 2017

Fingerprint

Transcription Factors
T-Lymphocytes
Transplants
Allografts
interferon regulatory factor-4
Chromatin
Transplantation
Ligands
Therapeutics

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

Cite this

Ablation of Transcription Factor IRF4 Promotes Transplant Acceptance by Driving Allogenic CD4+ T Cell Dysfunction. / Wu, Jie; Zhang, Hedong; Shi, Xiaomin; Xiao, Xiang; Fan, Yihui; Minze, Laurie J.; Wang, Jin; Ghobrial, Rafik M.; Xia, Jiahong; Sciammas, Roger; Li, Xian C.; Chen, Wenhao.

In: Immunity, 01.01.2017.

Research output: Contribution to journalArticle

Wu, Jie ; Zhang, Hedong ; Shi, Xiaomin ; Xiao, Xiang ; Fan, Yihui ; Minze, Laurie J. ; Wang, Jin ; Ghobrial, Rafik M. ; Xia, Jiahong ; Sciammas, Roger ; Li, Xian C. ; Chen, Wenhao. / Ablation of Transcription Factor IRF4 Promotes Transplant Acceptance by Driving Allogenic CD4+ T Cell Dysfunction. In: Immunity. 2017.
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