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

JOURNAL OF HEART AND LUNG TRANSPLANTATION

卷:40

Article

Wang, Guohua^1,2,3  Zou, Dawei^1,2  Wang, Yixuan^1,2,3  Gonzalez, Nancy M.^1,2  Yi, Stephanie G.^4,5  Li, Xian C.^1,2,5  Chen, Wenhao^1,2,5  Gaber, A. Osama^4,5 

[1] Houston Methodist Hosp, Houston Methodist Res Inst, Immunobiol & Transplant Sci Ctr, Dept Surg, Houston, TX 77030 USA

[2] Houston Methodist Hosp, Inst Acad Med, Houston, TX USA

[3] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Cardiovasc Surg, Wuhan, Peoples R China

[4] Houston Methodist Hosp, JC Walter Jr Transplant Ctr, Dept Surg, Houston, TX 77030 USA

[5] Cornell Univ, Weill Cornell Med, Dept Surg, New York, NY 10021 USA

关键词: B cells;    IRF4;    chronic rejection;    germinal center B cells;    transcriptional regulation;    donor-specific antibodies;    B cell development;   

DOI  :  10.1016/j.healun.2021.06.008

来源: Elsevier

【 摘 要 】

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 Irf4(gfp) 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 naive 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 naive 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. (C) 2021 International Society for Heart and Lung Transplantation. All rights reserved.

【 授权许可】

Free