Ablation of interferon regulatory factor 4 in T cells induces “memory” of transplant tolerance that is irreversible by immune checkpoint blockade

Hedong Zhang, Jie Wu, Dawei Zou, Xiang Xiao, Hui Yan, Xian Chang Li, Wenhao Chen

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

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 (IRF4) in T cells induced heart transplant acceptance by driving allogeneic CD4 + T cell dysfunction. Herein, we showed that heart-transplanted mice with T cell-specific IRF4 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 CD4 + 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 IRF4 represents a potential therapeutic strategy for driving intrinsic T cell dysfunction and achieving alloantigen-specific transplant tolerance.

Original languageEnglish (US)
Pages (from-to)884-893
Number of pages10
JournalAmerican Journal of Transplantation
Volume19
Issue number3
DOIs
StatePublished - Mar 2019

Keywords

  • T cell biology
  • animal models: murine
  • basic (laboratory) research/science
  • cellular biology
  • graft survival
  • immunobiology
  • organ transplantation in general
  • tolerance

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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