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