BAFF regulates T follicular helper cells and affects accumulation and IFNγ production in autoimmunity

Peripheral B-cell responses to foreign antigen is a tightly regulated process with multiple checkpoints that generate protective antibodies and prevent the development of autoantibodies (1). The coordinated interplay between antigen-specific B-cells and TFH cells is crucial in this process by establishing GCs that facilitate the selection and differentiation of memory B-cells and plasma cells (PC) that produce high-affinity antibodies (2, 3). It has been shown in mouse models of SLE that accumulation of TFH cells is a significant catalyst of autoantibody production and inhibiting TFH cell formation reduces disease (4). Therefore, mechanisms must exist that maintain TFH cell homeostasis under normal circumstances to avoid unchecked TFH activity, inhibiting the production of pathogenic autoantibodies that promotes autoimmunity. Family members belonging to the BAFF cytokine-receptor network (BCMA, BR3, TACI) have been closely linked to B-cell homeostasis and tolerance (5). Multiple innate immune cell types including dendritic cells produce BAFF (6). BR3 (but not BCMA) is expressed on mature B-cells, while PCs express BCMA and reduced levels of BR3. BAFF signaling through BR3 on mature B-cells is critical for their survival (7). In contrast, BCMA is critically required for survival of bone marrow PCs but dispensable for maintaining peripheral B-cell and PC numbers (8, 9). Increased levels of BAFF have been linked to loss of B-cell tolerance in both autoimmune mice and humans (10–13). Given that excess BAFF promotes survival and differentiation of autoreactive B-cells that arise in the GC reaction, we initially reasoned that a deficiency in BCMA of lupus-prone mice would deprive autoantibody-producing PCs of a key survival factor and therefore reduce autoantibody production. Paradoxically, we found that BCMA deficiency exacerbates the formation of autoantibody-secreting PCs in spleens of autoimmune-prone mice and the reasons for this effect is not understood (14). Despite evidence that BR3 is expressed on a subset of T cells (15–17), our knowledge of the physiologic importance of BAFF function in T cells in vivo is minimal. Studies in BAFF transgenic mice and arthritic mice demonstrated a role for BAFF in mediating proinflammatory CD4+ T cell responses (18, 19). However, the potential role for BAFF in TFH cell homeostasis is not known.