Azuma Miyuki
Department of Molecular Immunology, Tokyo Medical and Dental Univerisity, Graduate School, Tokyo, Japan.
Crit Rev Immunol. 2010;30(6):547-57. doi: 10.1615/critrevimmunol.v30.i6.40.
Glucocorticoid-induced TNF receptor-related protein (GITR) is expressed in regulatory T cells at high levels, but is also inducible in conventional effector T cells after activation. Initial studies using an agonistic anti- GITR mAb mislead this line of research with respect to the contribution of GITR stimulation on the function of regulatory T cells. In fact, GITR acts as a costimulatory receptor for both effector and regulatory T cells by enhancing effector and regulatory functions, respectively. Unlike other costimulatory ligands, GITR ligand (GITRL) expression on mature myeloid dendritic cells (DCs) is extremely limited and the GITR-GITRL pathway does not contribute markedly to direct interactions with T cells and antigen-presenting cells in the secondary lymphoid tissues. Rather, GITRL is constitutively expressed on parenchymal tissue cells and interacts with GITR expressed on tissue-infiltrating macrophages and DCs, or effector and regulatory T cells. Interactions with GITR and GITRL at local inflammatory sites induce site-specific production of cytokines and chemokines, resulting in control activation of tissue-infiltrating effector or regulatory cells and their migration. This review summarizes recent reports on the GITR-GITRL pathway, which controls both innate and adaptive immune responses.
糖皮质激素诱导的TNF受体相关蛋白（GITR）在调节性T细胞中高水平表达，但在传统效应T细胞激活后也可被诱导表达。最初使用激动性抗GITR单克隆抗体的研究在GITR刺激对调节性T细胞功能的贡献方面误导了这一研究方向。事实上，GITR分别通过增强效应和调节功能，作为效应T细胞和调节性T细胞的共刺激受体。与其他共刺激配体不同，成熟髓样树突状细胞（DC）上的GITR配体（GITRL）表达极其有限，并且GITR - GITRL途径对次级淋巴组织中与T细胞和抗原呈递细胞的直接相互作用贡献不大。相反，GITRL在实质组织细胞上组成性表达，并与组织浸润巨噬细胞和DC或效应T细胞和调节性T细胞上表达的GITR相互作用。在局部炎症部位与GITR和GITRL的相互作用诱导细胞因子和趋化因子的位点特异性产生，导致组织浸润效应细胞或调节细胞的受控激活及其迁移。本综述总结了关于GITR - GITRL途径的最新报道，该途径控制先天性和适应性免疫反应。
