Dong C, Juedes A E, Temann U A, Shresta S, Allison J P, Ruddle N H, Flavell R A
Howard Hughes Medical Institute, Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Nature. 2001 Jan 4;409(6816):97-101. doi: 10.1038/35051100.
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.
T淋巴细胞的激活和免疫功能受共刺激分子调控。CD28是B7基因产物的受体，在启动T细胞免疫反应中起主要作用。CTLA4与B7的亲和力更高，在T细胞激活后被诱导产生，并参与下调T细胞反应。诱导性共刺激分子（ICOS）是CD28/CTLA4家族的第三个成员，在活化的T细胞上表达。其配体B7H/B7RP-1在动物注射脂多糖后在B细胞和非免疫组织中表达。为了解ICOS在T细胞激活和功能中的作用，我们构建并分析了ICOS缺陷小鼠。我们在此表明，在没有ICOS的情况下，T细胞激活和增殖存在缺陷。此外，ICOS -/- T细胞在体外分化或体内启动时无法产生白细胞介素-4。用多种抗原免疫后，体液免疫反应需要ICOS。ICOS-/-小鼠对实验性自身免疫性脑脊髓炎的易感性大大增强，表明ICOS在炎症性自身免疫疾病中具有保护作用。
