Mahajan Simmi, Cervera Ana, MacLeod Megan, Fillatreau Simon, Perona-Wright Georgia, Meek Stephen, Smith Andrew, MacDonald Andrew, Gray David
Institute of Immunology and Infection Research, University of Edinburgh, Ashworth Laboratories, King's Buildings, Edinburgh, UK.
Eur J Immunol. 2007 Jul;37(7):1796-808. doi: 10.1002/eji.200636661.
We have addressed the role of the inducible costimulator (ICOS) in the development of T cell help for B cells and in the generation, survival and reactivation of memory CD4 T cells and B cells. We find that while T cell help for all antibody isotypes (including IgG2c) is impaired in ICOS knockout (ICOS-KO) mice, the IFN-gamma response is little affected, indicating a defect in helper function that is unrelated to cytokine production. In addition, the ICOS-negative T cells do not accumulate in B cell follicles. Secondary (memory), but not primary, clonal proliferation of antigen-specific B cells is impaired in ICOS-KO mice, as is the generation of secondary antibody-secreting cells. Analysis of endogenous CD4 memory cells in ICOS-KO mice, using MHC class II tetramers, reveals normal primary clonal expansion, formation of memory clones and long-term (10 wk) survival of memory cells, but defective expansion upon reactivation in vivo. The data point to a role of ICOS in supporting secondary, memory and effector T cell responses, possibly by influencing cell survival. The data also highlight differences in ICOS dependency of endogenous T cell proliferation in vivo compared to that of adoptively transferred TCR-transgenic T cells.
我们已经研究了诱导性共刺激分子（ICOS）在T细胞对B细胞的辅助作用发展过程中，以及在记忆性CD4 T细胞和B细胞的产生、存活及再激活过程中的作用。我们发现，虽然在ICOS基因敲除（ICOS-KO）小鼠中，T细胞对所有抗体亚型（包括IgG2c）的辅助作用均受损，但IFN-γ反应几乎未受影响，这表明辅助功能存在缺陷，且与细胞因子产生无关。此外，ICOS阴性T细胞不会在B细胞滤泡中积聚。在ICOS-KO小鼠中，抗原特异性B细胞的二次（记忆性）而非初次克隆增殖受损，二次抗体分泌细胞的产生也受到损害。使用MHC II类四聚体分析ICOS-KO小鼠中的内源性CD4记忆细胞，结果显示其初次克隆扩增正常、记忆克隆形成正常且记忆细胞长期（10周）存活，但在体内再激活时扩增存在缺陷。这些数据表明ICOS可能通过影响细胞存活，在支持二次、记忆性和效应性T细胞反应中发挥作用。这些数据还突出了内源性T细胞在体内增殖对ICOS的依赖性与过继转移的TCR转基因T细胞相比存在差异。
