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IRF4 ablation in B cells abrogates allogeneic B cell responses and prevents chronic transplant rejection
- Source :
- The Journal of Heart and Lung Transplantation. 40:1122-1132
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
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 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.
- Subjects :
- Graft Rejection
0301 basic medicine
Pulmonary and Respiratory Medicine
T cell
Mice
03 medical and health sciences
0302 clinical medicine
Plasma cell differentiation
medicine
Animals
B cell
Mice, Knockout
B-Lymphocytes
Mice, Inbred BALB C
Transplantation
biology
business.industry
Graft Survival
Germinal center
Skin Transplantation
Germinal Center
medicine.disease
Transplant rejection
Disease Models, Animal
030104 developmental biology
medicine.anatomical_structure
Hemocyanins
Interferon Regulatory Factors
Cancer research
biology.protein
Heart Transplantation
Surgery
Antibody
Cardiology and Cardiovascular Medicine
business
Haptens
030215 immunology
IRF4
Subjects
Details
- ISSN :
- 10532498
- Volume :
- 40
- Database :
- OpenAIRE
- Journal :
- The Journal of Heart and Lung Transplantation
- Accession number :
- edsair.doi.dedup.....8c1ef07476fa1ba4b0009817d4bc5947
- Full Text :
- https://doi.org/10.1016/j.healun.2021.06.008