Regulation of Alloimmunity by B Cells

About This Grant

Project Summary/Abstract Current state-of-the-art immunosuppressive strategies have significantly improved short-term graft survival rates, but they have failed to promote immunoregulation and improve long-term graft outcome. Although much research has been performed on CD4+ T cells in the process of rejection, B cells are well-established to be of great significance in alloimmunity. B cells function as antigen presenting cells to promote alloreactive T cell activation, they interact with activated T cell subsets and they differentiate into alloantibody producing plasma cells that elicit humoral rejection which rapidly accelerates graft failure. Nevertheless, distinct but rare subsets of B cells have also been identified to promote immunoregulation, and these regulatory B cells are postulated to have critical protective functions following human solid organ transplantation. In recently published studies, we observed that a regulatory receptor called Neuropilin-2 (NRP2) is expressed on distinct subsets of human and mouse B cells. In preliminary studies, we find that NRP2-expressing B cells have phenotypic features of B regulatory cells, and further that they have potential to suppress CD4+ T effector cell activation responses. In this R21 proposal, we plan to examine this possibility by profiling NRP2-expressing B cells and assessing their function to suppress alloimmune effector T cell activation. Furthermore, we will examine the effects of the NRP2 ligand Semaphorin3F (Sema3F) by profiling responsive genes in NRP2-expressing human and mouse B cells. The overall objective of this proposal is to evaluate whether Sema3F-NRP2 interactions promote immunoregulatory function in B cells. We will test the hypothesis that Semaphorin-induced signaling within NRP2-expressing B cells results in their differentiation into regulatory subsets that suppress CD4+ T effector cell activation following transplantation. We propose two specific aims in which we will: 1) profile NRP2 expression on subpopulations of human and mouse B cells to identify its function in B regulatory cell activity in vitro, and 2), determine whether NRP2-expressing B cells are of functional significance in the prevention of rejection and/or in long-term graft survival. Collectively, the proposed studies address a clinically relevant problem and our approach provides for cohesiveness to translate in vitro findings using human cells into relevant murine transplant models in vivo.