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ICOS co-stimulatory receptor is essential for T-cell activation and function


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 responses1,2. CTLA4, which binds B7 with a higher affinity, is induced after T-cell activation and is involved in downregulating T-cell responses3,4. The inducible co-stimulatory molecule (ICOS), a third member of the CD28/CTLA4 family, is expressed on activated T cells5,6. Its ligand B7H/B7RP-1 is expressed on B cells and in non-immune tissues after injection of lipopolysaccharide into animals6,7. 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.

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Figure 1: Generation of ICOS knockout mice.
Figure 2: Defective T-cell activation in vitro by ICOS-/- cells.
Figure 3: Defective cytokine production by ICOS-/- cells.
Figure 4: ICOS-deficient animals have normal infiltration of the lung with inflammatory cells but are defective in antibody responses after antigen challenges of the airway.
Figure 5: ICOS-deficient mice are severely susceptible to EAE.


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The authors thank C. L. Stewart for providing reagents; L. Evangelisti, D. Butkus, C. Hughes, J. Stein and M. Chen for technical assistance; E. Enyon for discussion; and F. Manzo for secretarial work. This work was supported by grants from the NIH (to R.A.F.), the National Multiple Sclerosis Society (to N.H.R.), the Sandler Program for Asthma Research (to R.A.F.) and the Howard Hughes Medical Institute. C.D. is a recipient of an Arthritis Investigator award, and J.A. and R.A.F. are Investigators of the Howard Hughes Medical Institute.

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Correspondence to Richard A. Flavell.

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Dong, C., Juedes, A., Temann, UA. et al. ICOS co-stimulatory receptor is essential for T-cell activation and function . Nature 409, 97–101 (2001).

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