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ICOS Contributes to T Cell Expansion in CTLA-4 Deficient Mice¹

Miranda E. A. T. van Berkel^*, Elise H. R. Schrijver^*, Frans M. A. Hofhuis^*, Arlene H. Sharpe, Anthony J. Coyle, Chris P. Broeren, Kiki Tesselaar^* and Mariëtte A. Oosterwegel^2,*

^* Department of Immunology, University Medical Center, Utrecht, The Netherlands; Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; Millennium Pharmaceuticals Inc., Cambridge, MA 02139; and University of Utrecht, Institute of Infectious Diseases and Immunology, Utrecht, The Netherlands

Both CD28 and ICOS are important costimulatory molecules that promote Ag-specific cellular and humoral immune reactions. Whereas CD28 is generally thought to be the most important molecule in the initiation of a T cell response, ICOS is considered to act during the effector phase. We have investigated the contribution of ICOS to T cell responses in the absence of CTLA-4-mediated inhibition. Mice lacking CTLA-4, which show spontaneous CD28-mediated CD4⁺ T cell activation, expansion and differentiation, were treated with antagonistic ICOS antibodies. Blocking the interaction between ICOS and its ligand B7RP-1 significantly reduced this aberrant T cell activation and caused a reduction in T cell numbers. In vitro analysis of CD4⁺ T cells from treated mice revealed that ICOS blockade significantly reduced Th1 differentiation, while Th2 differentiation was only moderately inhibited. Further in vitro stimulation experiments demonstrated that ICOS is able to induce proliferation of murine CD4⁺ and CD8⁺ T cells but only in the presence of IL-2. These results indicate that ICOS is not only important for T cell effector function but also contributes to the expansion phase of a T cell response in the presence of CD28 signaling.