T follicular helper cells contribute to autoimmunity through the BCMA-BAFF axis (BA2P.117)

Abstract

Abstract T follicular helper (TFH) cells are critical for the development of protective antibodies via germinal center B-cell responses; however, uncontrolled TFH cell expansion activates autoreactive B-cells to produce antibodies that cause autoimmunity. Although increased circulating level of the cytokine BAFF has been linked to loss of B-cell tolerance in systemic autoimmunity, the potential role for BAFF in TFH cell homeostasis is not known. B-cell maturation antigen (BCMA) is a receptor for BAFF and is critical for the development and survival of bone marrow plasma cells (PCs). Paradoxically, BCMA deficiency exacerbates the formation of autoantibody-secreting PCs in spleens of autoimmune-prone mice. Here, we show that TFH cells uniquely express BCMA and that the absence of BCMA in TFH cells enhances their numbers and responsiveness to BAFF, and in turn, drive autoantibody production. Moreover, circulating CD4+ T cells and TFH-like cells that express another BAFF receptor BR3 (but not BCMA) are elevated in SLE patients and positively correlate with disease severity. These results identify a new BCMA-BAFF axis in controlling TFH cell homeostasis and suggest that the balance between BCMA and BR3 signaling in TFH cells serves as an additional checkpoint of immune tolerance.