1. Howard Hughes Medical Institute, Section of Immunobiology, and
2. Yale University School of Medicine, New Haven, Connecticut 06520, USA
3. Department of Epidemiology and Public Health and Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA
4. Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California at Berkeley , Berkeley, California 94720, USA
5. These authors contributed equally to this work
6. Present address: Department of Immunology, University of Washington School of Medicine, Box 357650, Seattle, Washington 98195-7650, USA.

Correspondence to: Richard A. Flavell^1,6 Correspondence and requests for materials should be addressed to R.A.F. (e-mail: Email: richard.flavell@yale.edu).

Abstract

T-lymphocyte activation and immune function are regulated by co-stimulatory molecules. CD28, a receptor for B7 gene products, has a chief role in initiating T-cell immune responses^{1, 2}. CTLA4, which binds B7 with a higher affinity, is induced after T-cell activation and is involved in downregulating T-cell responses^{3, 4}. The inducible co-stimulatory molecule (ICOS), a third member of the CD28/CTLA4 family, is expressed on activated T cells^{5, 6}. Its ligand B7H/B7RP-1 is expressed on B cells and in non-immune tissues after injection of lipopolysaccharide into animals^{6, 7}. To understand the role of ICOS in T-cell activation and function, we generated and analysed ICOS-deficient mice. Here we show that T-cell activation and proliferation are defective in the absence of ICOS. In addition, ICOS ^-/- T cells fail to produce interleukin-4 when differentiated in vitro or when primed in vivo. ICOS is required for humoral immune responses after immunization with several antigens. ICOS^-/- mice showed greatly enhanced susceptibility to experimental autoimmune encephalomyelitis, indicating that ICOS has a protective role in inflammatory autoimmune diseases.

1. Howard Hughes Medical Institute, Section of Immunobiology, and
2. Yale University School of Medicine, New Haven, Connecticut 06520, USA
3. Department of Epidemiology and Public Health and Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA
4. Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California at Berkeley , Berkeley, California 94720, USA
5. These authors contributed equally to this work
6. Present address: Department of Immunology, University of Washington School of Medicine, Box 357650, Seattle, Washington 98195-7650, USA.

Correspondence to: Richard A. Flavell^1,6 Correspondence and requests for materials should be addressed to R.A.F. (e-mail: Email: richard.flavell@yale.edu).