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^highPD-1^highCD4⁺ 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. [ABSTRACT FROM AUTHOR]