title: Human T cell activation by costimulatory signal-deficient allogeneic cells induces inducible costimulator-expressing anergic T cells with regulatory cell activity.
abstract: Although immunoregulation by several types of regulatory T cells is now clearly established in mice, the demonstration of such regulatory T cells in humans has been proven more difficult. In this study we demonstrate the induction of anergic regulatory T cells during an MLR performed in the presence of blocking mAb to the costimulatory molecules CD40, CD80, and CD86. Despite this costimulation blockade, which totally blocks T cell proliferation and cytokine production, a nonproliferating T cell subpopulation was activated to express inducible costimulator (ICOS). These ICOS(+) cells were anergic when restimulated with unmanipulated allogeneic stimulator cells at the level of proliferation and Th1 and Th2 cytokine production, but they did produce IL-10. These ICOS-expressing cells also blocked the capacity of reciprocal ICOS-negative cells to proliferate and to produce cytokines. ICOS(+) anergic cells could suppress allogenic responses of either primed or naive T cells through inhibition of IL-2 gene transcription. Suppression was not mediated by IL-10 and did not require ICOS-ICOS ligand interaction, but depended on cell-cell contact. Thus, a subtype of regulatory T cells in human blood can be activated in the absence of costimulatory signals from CD40, CD80, and CD86, and they can be identified by expression of ICOS after activation.
authors.affiliation: Laboratory of Experimental Immunology, Catholic University of Leuven, Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Vermeiren
authors.forename: Jan L
authors.initials: JL
authors.lastname: Ceuppens
authors.forename: Marijke
authors.initials: M
authors.lastname: Van Ghelue
authors.forename: Peter
authors.initials: P
authors.lastname: Witters
authors.forename: Dominique
authors.initials: D
authors.lastname: Bullens
authors.forename: Hans Werner
authors.initials: HW
authors.lastname: Mages
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kroczek
authors.forename: Stefaan W
authors.initials: SW
authors.lastname: Van Gool
mesh_terms: D000328:Adult; D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D018122:B7-1 Antigen / Q000276:immunology; D051940:B7-2 Antigen; D019013:CD40 Antigens / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000276:immunology*; D005260:Female; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000276:immunology; D008875:Middle Aged; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015398:Signal Transduction / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497964:CD86 protein, human; C556692:ICOS protein, human; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D007376:Interleukin-2; D008024:Ligands; D008562:Membrane Glycoproteins; D012333:RNA, Messenger