T Follicular Regulatory (TFR) Cells Regulate B Cell Responses in Both, T-cell Dependent and Independent Pathways

Abstract

Abstract Production of high-affinity antibody-secreting plasma cells and memory B cells requires interaction of TFH cells with B cells in the follicle. TFR cells, a subset of Foxp3+ Tregs, localize into follicles, regulating GC responses. To elucidate the mechanisms and cellular targets used by TFR cells to suppress GC responses, we quantitated their function in vitro. In the absence of TFR cells, TFH from primed mice induce 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 differentiation and class switching in the anti-CD3 alone cultures, but moderately suppressed BCR-stimulated B cells. Under anti-CD3 conditions, IL-4−/− TFH cells did not promote B cell differentiation and class switching. In contrast, IL-21R−/− B cells differentiated into GC B cells with a reduced number of IgG1+ cells. When IL-4−/− TFH cells were co-cultured with IL-21R−/− B cells, both GC differentiation and class switching were reduced. Under anti-IgM/anti-CD3 conditions, IL-4−/− TFH cells promoted B cell differentiation, but class switching was reduced, while IL-21R−/− B cells differentiated normally into GC B cells, with reduced class switching. When B cells alone were stimulated in culture with either LPS or CpG, TFR cells did not block B cell proliferation, but their differentiation into plasma cells was reduced. These studies suggest that in vitro, TFR cells regulate GC responses primarily by acting on TFH cells by inhibiting cytokine production and CD40L expression, but can also directly suppress some aspects of B cell differentiation. Supported by the Intramural Research Program of the NIAID.