title: IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2.
abstract: T follicular regulatory (Tfr) cells control the magnitude and specificity of the germinal centre reaction, but how regulation is contained to ensure generation of high-affinity antibody is unknown. Here we show that this balance is maintained by the reciprocal influence of interleukin (IL)-2 and IL-21. The number of IL-2-dependent FoxP3+regulatory T cells is increased in the peripheral blood of human patients with loss-of-function mutations in the IL-21 receptor (IL-21R). In mice, IL-21:IL-21R interactions influence the phenotype of T follicular cells, reducing the expression of CXCR4 and inhibiting the expansion of Tfr cells after T-cell-dependent immunization. The negative effect of IL-21 on Tfr cells in mice is cell intrinsic and associated with decreased expression of the high affinity IL-2 receptor (CD25). Bcl-6, expressed in abundance in Tfr cells, inhibits CD25 expression and IL-21-mediated inhibition of CD25 is Bcl-6 dependent. These findings identify a mechanism by which IL-21 reinforces humoral immunity by restricting Tfr cell proliferation.
authors.affiliation: Department of Immunology, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia.|Department of Medicine, St Vincent's Clinical School, University of NSW, Sydney, New South Wales 2010, Australia.
authors.forename: Christoph
authors.identifier: 0000-0002-6975-6004
authors.initials: C
authors.lastname: Jandl
authors.affiliation: Department of Immunology, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia.|Department of Medicine, St Vincent's Clinical School, University of NSW, Sydney, New South Wales 2010, Australia.
authors.forename: Sue M
authors.initials: SM
authors.lastname: Liu
authors.affiliation: Division of Immunology and Genetics, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 2601, Australia.
authors.forename: Pablo F
authors.initials: PF
authors.lastname: Cañete
authors.affiliation: Department of Immunology, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia.
authors.forename: Joanna
authors.initials: J
authors.lastname: Warren
authors.affiliation: Department of Immunology, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia.
authors.forename: William E
authors.initials: WE
authors.lastname: Hughes
authors.affiliation: Department of Immunology, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia.
authors.forename: Alexis
authors.initials: A
authors.lastname: Vogelzang
authors.affiliation: Department of Immunology, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia.|Department of Medicine, St Vincent's Clinical School, University of NSW, Sydney, New South Wales 2010, Australia.
authors.forename: Kylie
authors.initials: K
authors.lastname: Webster
authors.affiliation: Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, Locked Bag 4001, Westmead, New South Wales 2145, Australia.|School of Women's and Children's Health, University of New South Wales, High Street, Randwick, Sydney, New South Wales 2031, Australia.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Craig
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-9806, USA.
authors.forename: Gulbu
authors.initials: G
authors.lastname: Uzel
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, 635 Barnhill Drive, MS 420, Indianapolis, Indiana 46202, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dent
authors.affiliation: Pediatric Hematology-Oncology and Bone Marrow Transplantation, Hadassah Hebrew University Hospital, Kiryat Hadassah, POB 12000, Jerusalem 91120, Israel.
authors.forename: Polina
authors.initials: P
authors.lastname: Stepensky
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center and University of Freiburg, Breisacher Strasse 117, 79106 Freiburg, Germany.
authors.forename: Bärbel
authors.initials: B
authors.lastname: Keller
authors.affiliation: Center for Chronic Immunodeficiency (CCI), University Medical Center and University of Freiburg, Breisacher Strasse 117, 79106 Freiburg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Warnatz
authors.affiliation: Department of Immunology, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia.|Department of Medicine, St Vincent's Clinical School, University of NSW, Sydney, New South Wales 2010, Australia.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Sprent
authors.affiliation: Department of Immunology, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia.|Department of Medicine, St Vincent's Clinical School, University of NSW, Sydney, New South Wales 2010, Australia.
authors.forename: Cecile
authors.initials: C
authors.lastname: King
mesh_terms: D000293:Adolescent; D000818:Animals; D049109:Cell Proliferation / Q000235:genetics*; D002648:Child; D005260:Female; D006801:Humans; D056724:Immunity, Humoral / Q000235:genetics* / Q000276:immunology; D007153:Immunologic Deficiency Syndromes / Q000235:genetics; D007223:Infant; D007376:Interleukin-2 / Q000276:immunology*; D053738:Interleukin-21 Receptor alpha Subunit / Q000235:genetics* / Q000276:immunology; D007378:Interleukins / Q000235:genetics* / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000276:immunology*; D019718:Receptors, CXCR4 / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D000098546:Interleukin-21
chemical_list: C514936:CXCR4 protein, mouse; C508117:IL21R protein, human; C508118:Il21r protein, mouse; D007376:Interleukin-2; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; D051560:Proto-Oncogene Proteins c-bcl-6; D019718:Receptors, CXCR4; D000098546:Interleukin-21