Riley J L, Blair P J, Musser J T, Abe R, Tezuka K, Tsuji T, June C H
Abramson Family Cancer Research Institute and Department of Molecular and Cellular Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
J Immunol. 2001 Apr 15;166(8):4943-8. doi: 10.4049/jimmunol.166.8.4943.
We investigated the relationship between ICOS, CD28, CTLA-4, and IL-2 to gain a better understanding of this family of costimulatory receptors in the immune response. Using magnetic beads coated with anti-CD3 and varying amounts of anti-ICOS and anti-CTLA-4 Abs, we show that CTLA-4 ligation blocks ICOS costimulation. In addition to inhibiting cellular proliferation, CTLA-4 engagement prevented ICOS-costimulated T cells from producing IL-4, IL-10, and IL-13. Both an indirect and direct mechanism of CTLA-4's actions were examined. First, CTLA-4 engagement on resting cells was found to indirectly block ICOS costimulation by interferring with the signals needed to induce ICOS cell surface expression. Second, on preactivated cells that had high levels of ICOS expression, CTLA-4 ligation blocked the ICOS-mediated induction of IL-4, IL-10, and IL-13, suggesting an interference with downstream signaling pathways. The addition of IL-2 not only overcame both mechanisms, but also greatly augmented the level of cellular activation suggesting synergy between ICOS and IL-2 signaling. This cooperation between ICOS and IL-2 signaling was explored further by showing that the minimum level of IL-2 produced by ICOS costimulation was required for T cell proliferation. Finally, exogenous IL-2 was required for sustained growth of ICOS-costimulated T cells. These results indicate that stringent control of ICOS costimulation is maintained initially by CTLA-4 engagement and later by a requirement for exogenous IL-2.
我们研究了诱导共刺激分子（ICOS）、细胞毒性T淋巴细胞相关抗原4（CTLA-4）、CD28和白细胞介素-2（IL-2）之间的关系，以便更好地理解免疫反应中这一族共刺激受体。使用包被抗CD3以及不同量抗ICOS和抗CTLA-4抗体的磁珠，我们发现CTLA-4的结合会阻断ICOS共刺激。除了抑制细胞增殖外，CTLA-4的结合还阻止了ICOS共刺激的T细胞产生IL-4、IL-10和IL-13。我们研究了CTLA-4作用的间接和直接机制。首先，发现静止细胞上CTLA-4的结合通过干扰诱导ICOS细胞表面表达所需的信号间接阻断ICOS共刺激。其次，在ICOS表达水平高的预激活细胞上，CTLA-4的结合阻断了ICOS介导的IL-4、IL-10和IL-13的诱导，提示对下游信号通路的干扰。IL-2的添加不仅克服了这两种机制，还极大地增强了细胞激活水平，提示ICOS和IL-2信号之间存在协同作用。通过显示ICOS共刺激产生的IL-2的最低水平是T细胞增殖所必需的，进一步探索了ICOS和IL-2信号之间的这种合作。最后，ICOS共刺激的T细胞持续生长需要外源性IL-2。这些结果表明，ICOS共刺激的严格控制最初通过CTLA-4的结合来维持，随后通过对外源性IL-2的需求来维持。
