Identifying Diversity Within Memory B Cell Populations

Abstract

New data reveal phenotypic differences in self-renewing vs. antibody-producing memory B cells. Identifying Diversity Within Memory B Cell Populations Citation: Zuccarino-Catania GV, Sadanand S, Weisel FJ, Tomayko MM, MengH, Kleinstein SH, et al. CD80 and PD-L2 define functionally distinct memory B cell subsets that are independent of antibody isotype. Nat Immunol 2014; 15: 631-617 Antibody-mediated rejection (AMR) can occur in the setting of apparently adequate immunosuppression, and alloantibody-mediated responses have become increasingly recognized as detrimental to graft function despite well-controlled cellular immune responses. Regardless of advances in our ability to characterize donor-specific antibodies and improved immunohistochemical staining of biopsies for associated pathology such as C4d deposition, little is known about the immunologic mechanisms governing the development of donor-specific antibodies. Depleting antibody therapy directed toward CD20, which is expressed on B cells but not on plasma cells, in some cases moderately decreased the levels of donor-specific antibodies but in general failed to eliminate anti-HLA antibodies. A key missing link in the development of effective strategies for AMR may lie in a better understanding of long-lived memory B lymphocytes and their relationship to plasma cell maintenance and survival. Recent studies byZuccarino-Catania et al presented in Nature Immunology reveal novel insights into the differentiation and function of these cells, and demonstrate that the memory B cell (MBC) pool is much more heterogeneous than previously appreciated. MBCs provide enhanced immunity during secondary exposure to foreign antigen. These long-lived cells can differentiate into antibody-forming cells (AFCs) and make new antibodies or proliferate within germinal centers to provide a renewed source of lasting B cell memory. The elegant studies byZuccarino-Catania et al address the long-standing question of whether the ability of MBCs to either self-renew or terminally differentiate in AFCs is compartmentalized into discrete subsets or is intrinsically wired homogenously into all memory B lymphocytes. Previous work in this field has suggested that isotype switching controls the pattern of MBC lineage differentiation into either self-renewing MBCs or AFCs. These studies concluded that isotype-switched MBCs differentiate into AFCs, while IgM+ MBCs are predisposed for self-renewal. New data byZuccarino-Catania et al now demonstrate that this functional heterogeneity is independent of isotype and that lineage commitment to either AFCs or self-renewing MBCs can be identified by the expression of two cell surface proteins, CD80 and PD-L2. Specifically, CD80+PD-L2+ MBCs were shown to terminally differentiate into AFCs but did not exhibit self-renewal properties or generate new germinal centers. In contrast, CD80−PD-L2− MBCs generated a few early AFCs then rapidly induced GC formation upon re-exposure to antigen. Similarly, CD80+PD-L2+ and CD80−PD-L2− MBCs exhibited gene expression profiles consistent with plasma cell and self-renewing MBC identity, respectively. Interestingly, this study also revealed that memory T cell–MBC cognate interactions during secondary responses greatly enhanced the differentiation of all lineages of MBCs. These results have important implications for transplantation. In both mouse models and human studies, the differentiation status of the B cell compartment is increasingly identified as an important determinant for graft outcome. While recent studies have identified an association between naive and transitional B cells and long-term allograft survival and/or operational tolerance, MBCs have been linked to graft rejection and graft loss in both acute and chronic AMR. A notable implication of the work presented by Zuccarino-Catania et al is that knowledge of the phenotypic profiles of these distinct compartments will pave the way for mechanistic studies in mouse and human to assess the contribution of these subsets to AMR. Further down the line, identification of discrete cell surface phenotypes of these subsets may allow for their individual therapeutic targeting, facilitating more individualized therapy for AMR following transplantation. Additionally, monitoring of antigen-specific B cells using the allo-MHC tetramer technology that is being developed in the field can now be assessed in distinct MBC subsets during AMR. It is possible that evaluation of the immunophenotypic differentiation status of B lymphocytes could prove to be useful for stratifying patient risk after solid organ transplantation. Furthermore, investigation into the impact of type of immunosuppression on MBC lineage commitment will shed light on the mechanisms of AMR in patients treated with distinct immunosuppressive regimens. In sum, the lack of understanding of the requirements for B cell survival, activation and effector function during transplantation becomes more apparent as waitlists of sensitized patients continue to grow. To this end, the basic biology of B cell activation and differentiation during response to alloantigens deserves further basic and clinical scrutiny. Dr. Iwakoshi is assistant professor, Division of Transplantation, Department of Surgery, Emory University School of Medicine in Atlanta, and Dr. Ford is associate professor at the Emory Transplant Center. She is also section editor for “Literature Watch.”