Manzotti Claire N, Tipping Helen, Perry Laura C A, Mead Karen I, Blair Patrick J, Zheng Yong, Sansom David M
MRC Centre for Immune Regulation, University of Birmingham Medical School, Vincent Drive, Birmingham B15 2TT, GB, UK.
Eur J Immunol. 2002 Oct;32(10):2888-96. doi: 10.1002/1521-4141(2002010)32:10<2888::AID-IMMU2888>3.0.CO;2-F.
CD28 and CTLA-4 are opposing regulators of T cell activation, triggered by the two ligands CD80 and CD86. How these ligands promote either T cell activation via CD28 or inhibition via CTLA-4 is not understood. Using CD80 and CD86 molecules expressed on transfected cells, we have identified a major difference between these ligands in that CD80 transfectants have the ability to inhibit activation of resting human peripheral blood T cells via interaction with CTLA-4, whereas CD86 transfectants do not. Rather, CTLA-4-CD86 interactions appear to contribute towards T cell proliferation. We also observed that CTLA-4 function is strongly influenced by TCR stimulation, effects being observed only at relatively low levels of TCR stimulation. The kinetics of CD80-CTLA-4 interactions revealed that CTLA-4 inhibition took place within the first 8 h of T cell stimulation, despite there being little measurable CTLA-4 expression on the majority T cells. However, significant amounts of CTLA-4 were observed in the CD25(+) CD4(+) subset of T cells which, when removed from the cultures, accounted for the CTLA-4 inhibition observed. Overall, these data provide evidence that CD80 and CD86 differ in their interactions with CTLA-4 and that CD80 appears to be the preferential inhibitory ligand for CTLA-4 working via a population of CD4(+) CD25(+) CTLA-4(+) regulatory T cells.
CD28和CTLA-4是T细胞活化的相反调节因子，由两种配体CD80和CD86触发。目前尚不清楚这些配体如何通过CD28促进T细胞活化或通过CTLA-4抑制T细胞活化。利用转染细胞上表达的CD80和CD86分子，我们发现了这些配体之间的一个主要差异，即CD80转染细胞能够通过与CTLA-4相互作用抑制静息人外周血T细胞的活化，而CD86转染细胞则不能。相反，CTLA-4与CD86的相互作用似乎有助于T细胞增殖。我们还观察到CTLA-4的功能受到TCR刺激的强烈影响，仅在相对较低水平的TCR刺激下才观察到这种效应。CD80与CTLA-4相互作用的动力学表明，尽管大多数T细胞上几乎没有可测量的CTLA-4表达，但CTLA-4的抑制作用在T细胞刺激的最初8小时内就发生了。然而，在T细胞的CD25(+) CD4(+)亚群中观察到大量的CTLA-4，当从培养物中去除该亚群时，就出现了观察到的CTLA-4抑制作用。总体而言，这些数据提供了证据，表明CD80和CD86与CTLA-4的相互作用不同，并且CD80似乎是CTLA-4通过一群CD4(+) CD25(+) CTLA-4(+)调节性T细胞发挥作用的优先抑制性配体。
