IRF4 ablation in B cells abrogates allogeneic B cell responses and prevents 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 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.