title: Regulatory T cells control antigen-specific expansion of Tfh cell number and humoral immune responses via the coreceptor CTLA-4.
abstract: CD4(+)Foxp3-expressing Treg cells, which constitutively express the inhibitory coreceptor CTLA-4, are indispensable for immune homeostasis. We determined the roles of Treg cells and T follicular regulatory (Tfr) cells in the control of humoral immune responses. Depletion of Treg cells, blocking of CTLA-4 or a Treg cell specific reduction in CTLA-4 expression, resulted in an increase in the formation of antigen-specific Tfh cells, germinal center (GC), and plasma and memory B cells after vaccination. In the absence of Treg cell-expressed CTLA-4, large numbers of Tfr cells were present but were unable to restrain Tfh cell and GC formation. Temporary Treg cell depletion during primary immunization was sufficient to enhance secondary immune responses. Treg cells directly inhibited, via CTLA-4, B cell expression of CD80 and CD86, which was essential for Tfh cell formation. Thus, Treg and Tfr cells control Tfh cell and germinal center development, via CTLA-4-dependent regulation of CD80 and CD86 expression.
authors.affiliation: Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan.
authors.forename: James Badger
authors.initials: JB
authors.lastname: Wing
authors.affiliation: Laboratory of Lymphocyte Differentiation, Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Ise
authors.affiliation: Laboratory of Lymphocyte Differentiation, Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kurosaki
authors.affiliation: Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan; Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan. Electronic address: shimon@ifrec.osaka-u.ac.jp.
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism; D051940:B7-2 Antigen / Q000235:genetics / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D018858:Germinal Center / Q000187:drug effects / Q000276:immunology*; D056724:Immunity, Humoral / Q000235:genetics; D007073:Immunoglobulin E / Q000378:metabolism; D007156:Immunologic Memory; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D014611:Vaccination
chemical_list: D019138:Antibodies, Blocking; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007073:Immunoglobulin E