title: CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement.
abstract: Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is an essential regulator of T-cell responses, and its absence precipitates lethal T-cell hyperactivity. However, whether CTLA-4 acts simply to veto the activation of certain clones or plays a more nuanced role in shaping the quality of T-cell responses is not clear. Here we report that T cells in CTLA-4-deficient mice show spontaneous T-follicular helper (T(FH)) differentiation in vivo, and this is accompanied by the appearance of large germinal centers (GCs). Remarkably, short-term blockade with anti-CTLA-4 antibody in wild-type mice is sufficient to elicit T(FH) generation and GC development. The latter occurs in a CD28-dependent manner, consistent with the known role of CTLA-4 in regulating the CD28 pathway. CTLA-4 can act by down-regulating CD80 and CD86 on antigen presenting cells (APCs), thereby altering the level of CD28 engagement. To mimic reduced CD28 ligation, we used mice heterozygous for CD28, revealing that the magnitude of CD28 engagement is tightly linked to the propensity for T(FH) differentiation. In contrast, other parameters of T-cell activation, including CD62L down-regulation and Ki67 expression, were relatively insensitive to altered CD28 level. Altered T(FH) generation as a result of graded reduction in CD28 was associated with decreased numbers of GC B cells and a reduction in overall GC size. These data support a model in which CTLA-4 control of immunity goes beyond vetoing T-cell priming and encompasses the regulation of T(FH) differentiation by graded control of CD28 engagement.
authors.affiliation: Institute of Immunity and Transplantation, University College London Division of Infection and Immunity, London, United Kingdom NW3 2PF; and.
authors.forename: Chun Jing
authors.initials: CJ
authors.lastname: Wang
authors.affiliation: Institute of Immunity and Transplantation, University College London Division of Infection and Immunity, London, United Kingdom NW3 2PF; and.
authors.forename: Frank
authors.initials: F
authors.lastname: Heuts
authors.affiliation: Institute of Immunity and Transplantation, University College London Division of Infection and Immunity, London, United Kingdom NW3 2PF; and.
authors.forename: Vitalijs
authors.initials: V
authors.lastname: Ovcinnikovs
authors.affiliation: Institute of Immunity and Transplantation, University College London Division of Infection and Immunity, London, United Kingdom NW3 2PF; and.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Wardzinski
authors.affiliation: Institute of Immunity and Transplantation, University College London Division of Infection and Immunity, London, United Kingdom NW3 2PF; and.
authors.forename: Chantelle
authors.initials: C
authors.lastname: Bowers
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, Headington, United Kingdom OX3 7FY.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Schmidt
authors.affiliation: Institute of Immunity and Transplantation, University College London Division of Infection and Immunity, London, United Kingdom NW3 2PF; and.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Kogimtzis
authors.affiliation: Institute of Immunity and Transplantation, University College London Division of Infection and Immunity, London, United Kingdom NW3 2PF; and.
authors.forename: Rupert
authors.initials: R
authors.lastname: Kenefeck
authors.affiliation: Institute of Immunity and Transplantation, University College London Division of Infection and Immunity, London, United Kingdom NW3 2PF; and.
authors.forename: David M
authors.initials: DM
authors.lastname: Sansom
authors.affiliation: Institute of Immunity and Transplantation, University College London Division of Infection and Immunity, London, United Kingdom NW3 2PF; and lucy.walker@ucl.ac.uk.
authors.forename: Lucy S K
authors.initials: LS
authors.lastname: Walker
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D018106:CD28 Antigens / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D060908:CTLA-4 Antigen / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology; D018858:Germinal Center / Q000166:cytology / Q000276:immunology; D006579:Heterozygote; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D018448:Models, Immunological; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; D008024:Ligands; C575895:MIRN17-92 microRNA, mouse; D035683:MicroRNAs
keywords: CD28; CTLA-4; T cell; autoimmunity; costimulation