Foxp3⁺ follicular regulatory T cells control the germinal center response

Follicular helper (T FH) cells provide crucial signals to germinal center B cells undergoing somatic hypermutation and selection that results in affinity maturation. Tight control of T FH numbers maintains self tolerance. We describe a population of Foxp3 + Blimp-1 + CD4 + T cells constituting 10-25% of the CXCR5 high PD-1 high CD4 + T cells found in the germinal center after immunization with protein antigens. These follicular regulatory T (T FR) cells share phenotypic characteristics with T FH and conventional Foxp3 + regulatory T (T reg) cells yet are distinct from both. Similar to T FH cells, T FR cell development depends on Bcl-6, SLAM-associated protein (SAP), CD28 and B cells; however, T FR cells originate from thymic-derived Foxp3 + precursors, not naive or T FH cells. T FR cells are suppressive in vitro and limit T FH cell and germinal center B cell numbers in vivo. In the absence of T FR cells, an outgrowth of non-antigen-specific B cells in germinal centers leads to fewer antigen-specific cells. Thus, the T FH differentiation pathway is co-opted by T reg cells to control the germinal center response.