Regulatory B cells are involved in many pathophysiological processes, such as promoting tolerance in autoimmunity and organ transplantation, but also reducing immune responses to cancer. Overall, many studies indicate that regulatory B cells, like regulatory T cells, play a crucial role in regulating the immune system in many circumstances. A growing body of evidence highlights the strong heterogeneity as well as a high functional plasticity of regulatory B-cell subsets, which challenge a unique and stable definition. However, a common function of regulatory B cells is to produce the immunoregulatory cytokine IL-10. While significant attention has been focused on defining the multiple phenotypes of regulatory B cells, there remains a critical need to understand the molecular triggers of regulatory B-cell functions. In experiments performed with human blood B cells, we have obtained preliminary data pointing to specific molecular drivers that control the generation of IL-10-producing regulatory B cells. Among them, we noticed the transcription factor c-MAF, a factor belonging to the activator protein-1 (AP-1) superfamily and known to modulate cytokine production in T cells and macrophages. To date, a function of c-MAF in B cells has not been reported. Results from our analyses suggest that in humans, c-MAF acts as an early regulator of the generation of IL-10-producing B cells with a plasmablast phenotype. In addition, a recent publication together with publicly available gene transcription data indicate that c-Maf can bind the Il10 gene promoter in murine B cells and that, among all mouse B-cell subsets, is most highly transcribed in plasmablasts. The present study aims to use a tissue- specific gene knock-out mouse model to explore and establish in vivo the role of c-Maf in the generation of antibody-secreting cells and IL-10-producing plasmablasts. Specifically, we propose to use established c-Maf- floxed mice and CD19-Cre mice to generate B-cell conditional c-Maf knock-out mice to test the following: 1) the function of c-Maf in the steady-state development of plasmablasts and the generation of antibody-secreting plasmablasts and plasma cells after immunization; and 2) the contribution of c-Maf to the generation of IL-10- producing regulatory B cells and plasmablasts. Furthermore, these studies will use a Salmonella infection model to test whether c-Maf contributes to the development of functional regulatory B cells that reduce critical immune responses. The proposed studies are significant because they are the first to investigate the role of c- Maf in B-cell biology and because they will lead to a better understanding of the molecular processes regulating, on one side, the development of plasmablasts and humoral immunity, and on the other, the generation of regulatory B cells that contribute to exacerbated or ineffective immunity.
The immune system protects our body from infections and cancers by using different cell types to kill off infected or transformed cells. Given this ability, the function of the immune system must be properly regulated to prevent unleashing its power on cells that are not infected or transformed, thus causing unwarranted tissue and organ damage. Our studies aim to resolve the genes that guide the development of a regulatory type of immune cell that suppresses unwarranted immune responses.
