Mouse inducible costimulatory molecule (ICOS) expression is enhanced by CD28 costimulation and regulates differentiation of CD4(+) T cells

The inducible costimulatory (ICOS) molecule is expressed by activated T cel ls 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 e xpression and its role in Th responses we developed anti-mouse ICOS mAbs an d ICOS-Ig fusion protein. Little ICOS is expressed by freshly isolated mous e T cells, but ICOS is rapidly up-regulated on most CD4(+) and CD8(+) T cel ls following stimulation of the TCR, Strikingly, ICOS up-regulation is sign ificantly reduced in the absence of CD80 and CD86 and can be restored by CD 28 stimulation, suggesting that CD28-CD80/CD86 interactions may optimize IC OS expression. Interestingly, TCR-transgenic T cells differentiated into Th 2 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 stimula tion 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 stimu lated with peptide and APC in the presence of ICOS-Ig or control Ig, When t he ICOS:B7h interaction was blocked by ICOS-Ig, CD4(+) T cells produced mor e IFN-gamma and less IL-4 and IL-10 than CD4(+) cells differentiated with c ontrol Ig, These results demonstrate that ICOS stimulation is important in T cell activation and that ICOS may have a particularly important role in d evelopment of Th2 cells.