T Follicular Regulatory (TFR) Cells Regulate B Cell Responses By Targeting TF Helper (TFH) Cells

Abstract

Abstract Interaction of TFH cells with B cells not only helps TFH to fully commit to this lineage, but also provides B cells with survival and differentiation cues. A GC response is critical for the development of an immune response against pathogens, but a dysregulated response could lead to autoantibody production. TFR cells, a subset of Foxp3+ Tregs, localize into follicles to regulate GC responses. To elucidate the mechanism (s) and cellular target (s) utilized by TFR cells to suppress GC responses, we quantitated TFR function in vitro. In the absence of TFR cells, TFH from primed mice induce both naive B cell differentiation into GC B cells and class switching in the presence of anti-CD3 alone or anti-IgM/anti-CD3 in a contact dependent manner. Addition of TFR cells from primed mice efficiently suppressed GC B cell proliferation, differentiation and class switching in the anti-CD3 alone cultures, but only moderately suppressed BCR-stimulated B cells. Under anti-CD3 conditions, IL-4-deficient TFH cells did not promote B cell differentiation and class switching. In contrast, IL-21R-deficient B cells differentiated into GC B cells with a reduced number of IgG1+ cells. When IL-4 deficient TFH cells were co-cultured with IL-21R-deficient B cells, both GC differentiation and class switching were reduced. Under anti-IgM/anti-CD3 conditions, IL-4-deficient TFH cells promoted B cell differentiation, but class switching was reduced, while IL-21R-deficient B cells differentiated normally into GC B cells, but class switching was reduced. These studies suggest that at least in vitro, TFR cells regulate the GC responses by acting directly on TFH cells most likely by inhibiting cytokine production.