Franko Jennifer L, Levine Alan D
Department of Pathology, Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH 44106-4952, USA.
J Leukoc Biol. 2009 Mar;85(3):526-38. doi: 10.1189/jlb.0808505. Epub 2008 Dec 18.
Engagement of the costimulatory protein ICOS activates effector/memory T cells in tissue by enhancing TCR-mediated proliferation and cytokine production. We now report that in an antigen-independent manner, ICOS also induces adhesion and spreading in human effector/memory T cells, consequently inhibiting cell migration. T cell spreading and elongation after ICOS ligation are accompanied by the formation of two types of actin-rich membrane protrusions: thin, finger-like structures similar to filopodia and short, discrete microspikes. Although filopodia/microspike formation occurs independently of the PI-3K signaling cascade, ICOS-mediated T cell elongation depends on PI-3K activity, which inhibits the accumulation of GTP-bound RhoA. Further inhibition of RhoA activation exacerbates the ICOS-mediated, elongated phenotype. We propose that in inflamed tissue, ICOS engagement by ICOS ligand on a professional or nonprofessional APC prevents the forward motility of the T cell by inhibiting RhoA-dependent uropod retraction. The resulting ICOS-induced T cell spreading and filopodia/microspike formation may promote antigen recognition by enhancing a T cell's scanning potential of an adherent APC surface.
共刺激蛋白ICOS的激活通过增强TCR介导的增殖和细胞因子产生来激活组织中的效应/记忆T细胞。我们现在报告，ICOS还以抗原非依赖的方式诱导人效应/记忆T细胞的黏附和铺展，从而抑制细胞迁移。ICOS连接后T细胞的铺展和伸长伴随着两种富含肌动蛋白的膜突出物的形成：类似于丝状伪足的细的、手指状结构和短的、离散的微刺。尽管丝状伪足/微刺的形成独立于PI-3K信号级联反应，但ICOS介导的T细胞伸长依赖于PI-3K活性，PI-3K活性抑制GTP结合的RhoA的积累。对RhoA激活的进一步抑制会加剧ICOS介导的伸长表型。我们提出，在炎症组织中，专业或非专业抗原呈递细胞（APC）上的ICOS配体与ICOS的结合通过抑制RhoA依赖的尾足回缩来阻止T细胞的向前运动。由此产生的ICOS诱导的T细胞铺展和丝状伪足/微刺形成可能通过增强T细胞对黏附APC表面的扫描能力来促进抗原识别。
