title: Foxp3+ follicular regulatory T cells control the germinal center response.
abstract: 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.
authors.affiliation: Cambridge Institute for Medical Research and the Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Linterman
authors.forename: Wim
authors.initials: W
authors.lastname: Pierson
authors.forename: Sau K
authors.initials: SK
authors.lastname: Lee
authors.forename: Axel
authors.initials: A
authors.lastname: Kallies
authors.forename: Shimpei
authors.initials: S
authors.lastname: Kawamoto
authors.forename: Tim F
authors.initials: TF
authors.lastname: Rayner
authors.forename: Monika
authors.initials: M
authors.lastname: Srivastava
authors.forename: Devina P
authors.initials: DP
authors.lastname: Divekar
authors.forename: Laura
authors.initials: L
authors.lastname: Beaton
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Hogan
authors.forename: Sidonia
authors.initials: S
authors.lastname: Fagarasan
authors.forename: Adrian
authors.initials: A
authors.lastname: Liston
authors.forename: Kenneth G C
authors.initials: KG
authors.lastname: Smith
authors.forename: Carola G
authors.initials: CG
authors.lastname: Vinuesa
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D018858:Germinal Center / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051560:Proto-Oncogene Proteins c-bcl-6; D054380:Receptors, CXCR5 / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D017634:Self Tolerance / Q000276:immunology*; D018709:Statistics, Nonparametric; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000502:physiology
chemical_list: C490010:Bcl6 protein, mouse; C095085:CXCR5 protein, human; D004268:DNA-Binding Proteins; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D054380:Receptors, CXCR5; D012097:Repressor Proteins; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1