Balance of chemokine entry and exit signals controls T cell accumulation in skin

随着拟议的研究科学家发展奖，申请人将建立在她以前的 在抗原和趋化因子调节T细胞迁移和免疫方面的经验来研究T细胞 使用体内皮肤炎症模型进行再循环。Andrew D. Luster，MD，PhD，at 马萨诸塞州总医院将提供一个刺激的环境，以进一步候选人的科学 实现独立调查的最终目标。拟定的研究将 为申请人提供了机会，以检查趋化因子在调节 炎症皮肤中T细胞的迁移命运。 T细胞从血流进入组织和T细胞从组织退出进入传入淋巴控制 淋巴细胞在外周部位的积累及其参与免疫/炎症 反应.几种单个趋化因子在指导T细胞进入和离开淋巴细胞的交通中的作用， 皮肤已被鉴定。然而，不同趋化因子信号之间的相互作用在控制 T细胞通过皮肤的转运仍然完全未知。在这里，我们假设， 趋化因子进入、保留和退出信号调节效应/记忆T细胞在细胞内的积累， 皮肤在这些拟议的研究中，我们将使用迟发型超敏反应和过敏性皮炎模型， 1)研究调节炎症皮肤中效应/记忆T细胞积累的机制。 我们将通过用CFSE标记体内皮肤T细胞来追踪反应T细胞的迁移， 确定皮肤中CFSE+ T细胞的趋化因子受体表达谱， 那些继续通过皮肤迁移到引流淋巴结; 2）确定 外周组织中效应/记忆T细胞抗原识别对趋化因子受体表达的影响 以及它们在皮肤中的保留与迁移到传入淋巴中的关系; 3）试图推翻皮肤中的平衡。 使用基因改变的T细胞和缺乏或缺乏趋化因子受体的小鼠， 过表达趋化因子受体或趋化因子配体。这些研究的结果将进一步 阐明调节T细胞通过组织转运的机制，可能有利于治疗 大的T细胞浸润物在外周组织中不适当地积聚的病理状况。

With the proposed Research Scientist Development Award, the applicant will build upon her prior experience in antigen and chemokine regulation of T cell migration and immunity to study T cell recirculation using in vivo models of skin inflammation. The laboratory of Andrew D. Luster, MD, PhD, at Massachusetts General Hospital will provide a stimulating environment to further the candidate's scientific development toward achieving her ultimate goal of independent investigation. The proposed study will provide the applicant with the opportunity to examine the interplay of chemokines in regulating the migratory fate of T cells in inflamed skin. Both T cell entry into tissues from the bloodstream and T cell exit from tissues into afferent lymph control the accumulation of lymphocytes at peripheral sites and their participation in immune/inflammatory reactions. The roles of several individual chemokines in directing the traffic of T cell entry and exit from the skin have been characterized. However, the interplay between different chemokine signals in controlling the transit of T cells through skin remains completely unknown. Here, we hypothesize that a balance in chemokine entry, retention, and exit signals regulates the accumulation of effector/memory T cells within skin. In these proposed studies, we will use delayed type hypersensitivity and allergic dermatitis models to 1) Investigate the mechanisms that regulate the accumulation of effector/memory T cells in inflamed skin. We will track the migration of responding T cells by labelling cutaneous T cells in vivo with CFSE and determine the chemokine receptor expression profiles of CFSE+ T cells that remain in the skin, versus those that continue to migrate through the skin to draining lymph nodes; 2) Determine the consequence of effector/memory T cell antigen recognition in peripheral tissues on their expression of chemokine receptors and their retention in skin versus migration into afferent lymph; 3) Attempt to override the balance in chemokine receptor responsiveness using genetically altered T cells and mice that either lack or overexpress chemokine receptors or chemokine ligands. Results from these studies should further elucidate the mechanisms that regulate T cell transit through tissues and might benefit the treatment of pathological conditions in which large T cell infiltrates accumulate inappropriately in peripheral tissues.