IRF4 ablation in B cells abrogates allogeneic B cell responses and prevents chronic transplant rejection.
J Heart Lung Transplant
; 40(10): 1122-1132, 2021 10.
Article
en En
| MEDLINE
| ID: mdl-34253454
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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Linfocitos B
/
Trasplante de Corazón
/
Trasplante de Piel
/
Factores Reguladores del Interferón
/
Rechazo de Injerto
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
J Heart Lung Transplant
Asunto de la revista:
CARDIOLOGIA
/
TRANSPLANTE
Año:
2021
Tipo del documento:
Article