follicular regulatory T cells control the germinal center response

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