title: Mouse inducible costimulatory molecule (ICOS) expression is enhanced by CD28 costimulation and regulates differentiation of CD4+ T cells.
abstract: The inducible costimulatory (ICOS) molecule is expressed by activated T cells and has homology to CD28 and CD152. ICOS binds B7h, a molecule expressed by APC with homology to CD80 and CD86. To investigate regulation of ICOS expression and its role in Th responses we developed anti-mouse ICOS mAbs and ICOS-Ig fusion protein. Little ICOS is expressed by freshly isolated mouse T cells, but ICOS is rapidly up-regulated on most CD4(+) and CD8(+) T cells following stimulation of the TCR. Strikingly, ICOS up-regulation is significantly reduced in the absence of CD80 and CD86 and can be restored by CD28 stimulation, suggesting that CD28-CD80/CD86 interactions may optimize ICOS expression. Interestingly, TCR-transgenic T cells differentiated into Th2 expressed significantly more ICOS than cells differentiated into Th1. We used two methods to investigate the role of ICOS in activation of CD4(+) T cells. First, CD4(+) cells were stimulated with beads coated with anti-CD3 and either B7h-Ig fusion protein or control Ig fusion protein. ICOS stimulation enhanced proliferation of CD4(+) cells and production of IFN-gamma, IL-4, and IL-10, but not IL-2. Second, TCR-transgenic CD4(+) T cells were stimulated with peptide and APC in the presence of ICOS-Ig or control Ig. When the ICOS:B7h interaction was blocked by ICOS-Ig, CD4(+) T cells produced more IFN-gamma and less IL-4 and IL-10 than CD4(+) cells differentiated with control Ig. These results demonstrate that ICOS stimulation is important in T cell activation and that ICOS may have a particularly important role in development of Th2 cells.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: McAdam
authors.forename: T T
authors.initials: TT
authors.lastname: Chang
authors.forename: A E
authors.initials: AE
authors.lastname: Lumelsky
authors.forename: E A
authors.initials: EA
authors.lastname: Greenfield
authors.forename: V A
authors.initials: VA
authors.lastname: Boussiotis
authors.forename: J S
authors.initials: JS
authors.lastname: Duke-Cohan
authors.forename: T
authors.initials: T
authors.lastname: Chernova
authors.forename: N
authors.initials: N
authors.lastname: Malenkovich
authors.forename: C
authors.initials: C
authors.lastname: Jabs
authors.forename: V K
authors.initials: VK
authors.lastname: Kuchroo
authors.forename: V
authors.initials: V
authors.lastname: Ling
authors.forename: M
authors.initials: M
authors.lastname: Collins
authors.forename: A H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: G J
authors.initials: GJ
authors.lastname: Freeman
mesh_terms: D000276:Adjuvants, Immunologic / Q000502:physiology*; D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D001667:Binding, Competitive / Q000235:genetics / Q000276:immunology; D018106:CD28 Antigens / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D016207:Cytokines; C556694:Icos protein, mouse; C400230:Icosl protein, mouse; D007136:Immunoglobulins; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D008024:Ligands; D011506:Proteins; D011993:Recombinant Fusion Proteins