Mouse Inducible Costimulatory Molecule (ICOS) Expression Is Enhanced by CD28 Costimulation and Regulates Differentiation of CD4+ T Cells

• Published in: The Journal of immunology (1950) 2000-11, Vol.165 (9), p.5035-5040
• Main Authors: McAdam, Alexander J, Chang, Tammy T, Lumelsky, Anna E, Greenfield, Edward A, Boussiotis, Vassiliki A, Duke-Cohan, Jonathan S, Chernova, Tatyana, Malenkovich, Nelly, Jabs, Claudia, Kuchroo, Vijay K, Ling, Vincent, Collins, Mary, Sharpe, Arlene H, Freeman, Gordon J
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - physiology; Animals; Antigens, Differentiation, T-Lymphocyte - biosynthesis; Antigens, Differentiation, T-Lymphocyte - immunology; Antigens, Differentiation, T-Lymphocyte - metabolism; Antigens, Differentiation, T-Lymphocyte - physiology; Binding, Competitive - genetics; Binding, Competitive - immunology; CD28 Antigens - physiology; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell Differentiation - immunology; Cytokines - biosynthesis; Immunoglobulins - genetics; Immunoglobulins - metabolism; Immunoglobulins - pharmacology; Inducible T-Cell Co-Stimulator Ligand; Inducible T-Cell Co-Stimulator Protein; Ligands; Lymphocyte Activation - immunology; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, Transgenic; Proteins - genetics; Proteins - metabolism; Proteins - pharmacology; Proteins - physiology; Recombinant Fusion Proteins - immunology; Recombinant Fusion Proteins - metabolism; Recombinant Fusion Proteins - pharmacology; Th1 Cells - immunology; Th1 Cells - metabolism; Th2 Cells - immunology; Th2 Cells - metabolism; Up-Regulation - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.165.9.5035

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.