Foxp3(+) follicular regulatory T cells control T follicular helper cells and 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 germinal center after immunization. These follicular regulatory T cells (T(FR)) share phenotypic characteristics with T(FH) and conventional Foxp3(+) regulatory T cells (T(reg)) yet are distinct from either. Similar to T(FH) cells, T(FR) development depends on Bcl-6, SAP, CD28 and B cells; however T(FR) originate from thymic-derived Foxp3(+) precursors, not naïve or T(FH) cells. T(FR) are suppressive in vitro and limit T(FH) and germinal center B cell numbers in vivo. In the absence of T(FR), an outgrowth of non-antigen-specific B cells in germinal centers leads to fewer antigen-specific cells. Thus, T(reg) cells use the T(FH) differentiation pathway to produce specialized suppressor cells that control the germinal center response.