title: ICOS cooperates with CD28, IL-2, and IFN-gamma and modulates activation of human naïve CD4+ T cells.
abstract: Several sets of data indicate that ICOS regulates cytokine production in activated T cells, but is less effective on naïve T cells. This work evaluates ICOS function in human naïve CD4+ T cells through an assessment of the effect of soluble forms of the ICOS and CD28 physiological ligands on activation driven by anti-CD3 mAb. ICOS strikingly potentiated secretion of IL-2, IFN-gamma, IL-10, and TNF-alpha, but not IL-4, promoted by optimal stimulation of CD3+CD28, and it was the key switching-factor of activation when cells received suboptimal stimulation of CD3+CD28 or stimulation of CD3 alone in the presence of exogenous IL-2. In these conditions, blockade of IL-2 and IFN-gamma showed that ICOS builds up a positive feedback loop with IFN-gamma, which required IL-2 and was inhibited by IL-4. By contrast, in the absence of CD28 triggering or exogenous IL-2, ICOS-induced costimulation mainly supported expression of TGF-beta1 and FoxP3 and differentiation of regulatory T cells capable to inhibit proliferation of naïve CD4+ T cells driven by allogeneic cells. These data suggest that ICOS favors differentiation of Th effector cells when cooperates with appropriate activation stimuli such as CD3+CD28 or CD3+IL-2, whereas it supports differentiation of regulatory T cells when costimulatory signals are insufficient.
authors.affiliation: Interdisciplinary Research Center of Autoimmune Diseases and Department of Medical Sciences, "A. Avogadro" University of Eastern Piedmont at Novara, Novara, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Mesturini
authors.forename: Stefania
authors.initials: S
authors.lastname: Nicola
authors.forename: Annalisa
authors.initials: A
authors.lastname: Chiocchetti
authors.forename: Ilaria Seren
authors.initials: IS
authors.lastname: Bernardone
authors.forename: Luca
authors.initials: L
authors.lastname: Castelli
authors.forename: Thea
authors.initials: T
authors.lastname: Bensi
authors.forename: Massimo
authors.initials: M
authors.lastname: Ferretti
authors.forename: Cristoforo
authors.initials: C
authors.lastname: Comi
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
authors.forename: Josè Maria
authors.initials: JM
authors.lastname: Rojo
authors.forename: Junji
authors.initials: J
authors.lastname: Yagi
authors.forename: Umberto
authors.initials: U
authors.lastname: Dianzani
mesh_terms: D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D015153:Blotting, Western; D018106:CD28 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis*; D005455:Fluorescent Antibody Technique; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology*
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D016207:Cytokines; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D007376:Interleukin-2; D007371:Interferon-gamma