IRF4 ablation in B cells abrogates allogeneic B cell responses and prevents chronic transplant rejection

Guohua Wang, Dawei Zou, Yixuan Wang, Nancy M. Gonzalez, Stephanie G. Yi, Xian C. Li, Wenhao Chen, A. Osama Gaber

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

BACKGOUND: B cells contribute to chronic transplant rejection by producing donor-specific antibodies and promoting T cell response, but how these processes are regulated at the transcriptional level remains unclear. Herein, we investigate the role of transcription factor interferon regulatory factor 4 (IRF4) in controlling B cell response during chronic transplant rejection. METHODS: We generated the Irf4gfp reporter mice to determine IRF4 expression in B cell lineage. We then used mice with B cell-specific IRF4 deletion to define the role of IRF4 in B cell response after NP-KLH immunization or allogeneic heart transplantation. In particular, graft survival and histology, as well as B and T cell responses, were evaluated after transplantation. RESULTS: IRF4 is dynamically expressed at different stages of B cell development and is absent in germinal center (GC) B cells. However, IRF4 ablation in the B cell lineage primarily eliminates GC B cells in both naïve and NP-KLH immunized mice. In the transplantation setting, IRF4 functions intrinsically in B cells and governs allogeneic B cell responses at multiple levels, including GC B cell generation, plasma cell differentiation, donor-specific antibody production, and support of T cell response. B cell-specific IRF4 deletion combined with transient CTLA4-Ig treatment abrogates acute and chronic cardiac allograft rejection in naïve recipient mice but not in donor skin-sensitized recipients. CONCLUSIONS: B cells require IRF4 to mediate chronic transplant rejection. IRF4 ablation in B cells abrogates allogeneic B cell responses and may also inhibit the ability of B cells to prime allogenic T cells. Targeting IRF4 in B cells represents a potential therapeutic strategy for eliminating chronic transplant rejection.

Original languageEnglish (US)
Pages (from-to)1122-1132
Number of pages11
JournalJournal of Heart and Lung Transplantation
Volume40
Issue number10
DOIs
StatePublished - Oct 2021

Keywords

  • B cell development
  • B cells
  • IRF4
  • chronic rejection
  • donor-specific antibodies
  • germinal center B cells
  • transcriptional regulation

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine
  • Transplantation

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