Notch2+ Marginal zone B cell depletion decreases antigen shuttle to Follicular Dendritic cells and reduces alloantibody production

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Abstract Chronic antibody-mediated rejection (CAMR) is a major cause of allograft loss. Most anti-rejection therapies target T cells and novel treatments to suppress CAMR are needed. Notch2+ Marginal zone (MZ) B cells have a key role in rapidly generating antibodies and facilitating the shuttle of antigens to follicular dendritic cells (FDCs). The FDC:B cell interaction is crucial to the formation of memory B cells and long-lived plasma cells. To evaluate the role of Notch2+ MZ B cells in transplantation, we utilize a mouse model of kidney transplantation, in which HLA-A2-expressing allografts are transplanted into B6 recipients. Here, we demonstrate that the anti-Notch2 treatment depletes MZ B cells and decreases pathological features of alloantibody-mediated rejection. Mechanistically, the anti-Notch2 treatment decreases plasma cells and the formation of donor-specific antibodies abrogates C4d deposition and reduces graft-infiltrating NK cells. Moreover, the Notch2+ MZ B cell depletion decreases the shuttling of antigens to FDCs as evidenced by the reduction of antigen (HLA.A2+) within FDCs (CD35+) clusters. Thus, Notch2+ MZ B cell depletion reduces alloantibody responses by decreasing alloantigen shutting to FDCs, leading to fewer signs of antibody-mediated graft rejection. Further elucidating the role of the Notch2 pathway will be important to the development of novel therapeutic strategies to prevent alloantibody production.

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