Letschka Thomas, Kollmann Veronika, Pfeifhofer-Obermair Christa, Lutz-Nicoladoni Christina, Obermair Gerald J, Fresser Friedrich, Leitges Michael, Hermann-Kleiter Natascha, Kaminski Sandra, Baier Gottfried
Department for Medical Genetics, Innsbruck Medical University, Innsbruck, Austria.
Blood. 2008 Dec 1;112(12):4617-27. doi: 10.1182/blood-2007-11-121111. Epub 2008 Sep 16.
The antigen-specific interaction of a T cell with an antigen-presenting cell (APC) results in the formation of an immunologic synapse (IS) between the membranes of the 2 cells. beta(2) integrins on the T cell, namely, leukocyte function-associated antigen 1 (LFA-1) and its counter ligand, namely, immunoglobulin-like cell adhesion molecule 1 (ICAM-1) on the APC, critically stabilize this intercellular interaction. The small GTPase Rap1 controls T-cell adhesion through modulating the affinity and/or spatial organization of LFA-1; however, the upstream regulatory components triggered by the T-cell receptor (TCR) have not been resolved. In the present study, we identified a previously unknown function of a protein kinase C- theta (PKC-theta)/RapGEF2 complex in LFA-1 avidity regulation in T lymphocytes. After T-cell activation, the direct phosphorylation of RapGEF2 at Ser960 by PKC- theta regulates Rap1 activation as well as LFA-1 adhesiveness to ICAM-1. In OT-II TCR-transgenic CD4(+) T cells, clustering of LFA-1 after antigen activation was impaired in the absence of PKC- theta. These data define that, among other pathways acting on LFA-1 regulation, PKC- theta and its effector RapGEF2 are critical factors in TCR signaling to Rap1. Taken together, PKC- theta sets the threshold for T-cell activation by positively regulating both the cytokine responses and the adhesive capacities of T lymphocytes.
T细胞与抗原呈递细胞（APC）之间的抗原特异性相互作用导致这两种细胞的膜之间形成免疫突触（IS）。T细胞上的β₂整合素，即白细胞功能相关抗原1（LFA-1）及其在APC上的配对配体，即免疫球蛋白样细胞粘附分子1（ICAM-1），对这种细胞间相互作用起到关键的稳定作用。小GTP酶Rap1通过调节LFA-1的亲和力和/或空间组织来控制T细胞黏附；然而，由T细胞受体（TCR）触发的上游调节成分尚未明确。在本研究中，我们在T淋巴细胞的LFA-1亲和力调节中鉴定出蛋白激酶C-θ（PKC-θ）/RapGEF2复合物的一种先前未知的功能。T细胞激活后，PKC-θ使RapGEF2的丝氨酸960位点直接磷酸化，从而调节Rap1激活以及LFA-1与ICAM-1的黏附性。在OT-II TCR转基因CD4⁺ T细胞中，在缺乏PKC-θ的情况下，抗原激活后LFA-1的聚集受到损害。这些数据表明，在作用于LFA-1调节的其他途径中，PKC-θ及其效应物RapGEF2是TCR向Rap1信号传导的关键因素。综上所述，PKC-θ通过正向调节T淋巴细胞的细胞因子反应和黏附能力来设定T细胞激活的阈值。
