The role of beta1 integrin in modulating gut-homing alpha4beta7 on T cells

描述（由申请方提供）：整合素是高度参与指导T细胞位点特异性归巢的细胞表面粘附分子。该提案将研究T细胞获得和调节整合素表达的分子机制，从而促进组织特异性靶向。T细胞活化后，肠外归巢整合素α 4 β 1和肠归巢整合素α 4 β 7参与指导T细胞的靶向迁移。然而，其表达调控的分子机制还不清楚。由于这两种整合素都参与了自身免疫性疾病期间T细胞的运输，因此更深入地了解它们的调节具有重要的临床意义。整合素调节与NIDDK的使命特别相关，因为整合素参与炎症性肠病的发病机制。初步数据表明，β 1整联蛋白的表达可以调节α 4 β 7整联蛋白的表达，从而改变T细胞归巢偏好。利用新的小鼠模型系统，将评估β 1整联蛋白表达导致肠道归巢α 4 β 7表达调节的机制。将评估缺乏或过表达β 1整联蛋白的T细胞介导肠道炎症的能力。最近的数据表明，维生素A和维生素D代谢物在通过调节细胞表面粘附分子调节T细胞靶向中的相反作用。考虑到这一点，将通过一系列体外和体内活化研究探索β 1整联蛋白表达在T细胞上调节的具体机制。将特别关注维生素D在β 1整合素表达调节中的作用。研究与公共卫生的相关性：拟议的工作将扩大对整合素表达的理解，从而调节T细胞的归巢。通过确定T细胞调节整合素表达的机制，有可能特异性地控制T细胞的运输！这直接应用于T细胞调节疗法和更有效的免疫方案的开发。

DESCRIPTION (provided by the applicant): Integrins are cell surface adhesion molecules highly involved in directing site-specific homing of T cells. This proposal will investigate the molecular mechanisms by which T cells acquire and regulate integrin expression, thus promoting tissue-specific targeting. Following T cell activation, the extra-intestinal homing integrin alpha4beta1 and the gut-homing integrin alpha4beta7 are involved in directing the targeted migration of T cells. However, the molecular mechanism by which their expression is regulated is not well understood. As both of these integrins are involved in trafficking of T cells during autoimmune disease, a deeper understanding of their regulation is of great clinical significance. Integrin regulation is especially relevant to the mission of the NIDDK because integrins are involved in the pathogenesis of inflammatory bowel disease. Preliminary data suggests that expression of betal integrin can modulate alpha4beta7 integrin expression and thus alter T cell homing preference. Utilizing a novel mouse model system, the mechanism by which betal integrin expression results in modulation of gut-homing alpha4beta7 expression will be evaluated. The ability of T cells lacking or overexpressing betal integrin to mediate intestinal inflammation will be assessed. Recent data suggests opposing roles for vitamin A and vitamin D metabolites in regulation of T cell targeting through modulation of cell surface adhesion molecules. With this in mind, the specific mechanism by which betal integrin expression is regulated on T cells will be explored through a series of in vitro and in vivo activation studies. Particular attention will be devoted to the role of vitamin D in the regulation of betal integrin expression. Relevance of research to public health: The proposed work will expand upon the understanding of how integrin expression and thus homing of T cells is regulated. By determining the mechanism by which T cells regulate integrin expression, it may become possible to specifically control the trafficking of T cells! This has direct application to the development of T cell-modulating therapeutics and more effective immunization protocols.