Guohua Wang1, Dawei Zou2, Yixuan Wang1, Nancy M Gonzalez2, Stephanie G Yi3, Xian C Li4, Wenhao Chen5, A Osama Gaber3. 1. Immunobiology & Transplant Science Center, Department of Surgery, Houston Methodist Research Institute & Institute for Academic Medicine, Houston Methodist Hospital, Houston, Texas; Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 2. Immunobiology & Transplant Science Center, Department of Surgery, Houston Methodist Research Institute & Institute for Academic Medicine, Houston Methodist Hospital, Houston, Texas. 3. Department of Surgery, J. C. Walter Jr. Transplant Center, Houston Methodist Hospital, Houston, Texas; Department of Surgery, Weill Cornell Medicine, Cornell University, New York, New York. 4. Immunobiology & Transplant Science Center, Department of Surgery, Houston Methodist Research Institute & Institute for Academic Medicine, Houston Methodist Hospital, Houston, Texas; Department of Surgery, Weill Cornell Medicine, Cornell University, New York, New York. 5. Immunobiology & Transplant Science Center, Department of Surgery, Houston Methodist Research Institute & Institute for Academic Medicine, Houston Methodist Hospital, Houston, Texas; Department of Surgery, Weill Cornell Medicine, Cornell University, New York, New York. Electronic address: wchen@houstonmethodist.org.
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.
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.
Authors: Laura Barrio; Sara Román-García; Ester Díaz-Mora; Ana Risco; Rodrigo Jiménez-Saiz; Yolanda R Carrasco; Ana Cuenda Journal: Front Cell Dev Biol Date: 2020-03-24