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.