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

有了拟议的研究科学家发展奖，申请者将在她之前的基础上 抗原和趋化因子调节T细胞迁移和免疫研究的体会 利用活体皮肤炎症模型进行再循环。安德鲁·D·卢斯特博士的实验室，位于 马萨诸塞州综合医院将提供一个刺激的环境，以促进候选人的科学 朝着实现她独立调查的最终目标的方向发展。拟议的研究将 使申请人有机会研究趋化因子在调节 T细胞在炎症皮肤中的迁移命运。 T细胞从血流进入组织，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聚集及其参与免疫/炎症反应 反应。几种单独的趋化因子在引导T细胞进出的交通中的作用 皮肤已经被刻画出来了。然而，不同趋化因子信号之间在调控中的相互作用 T细胞通过皮肤的转运仍是完全未知的。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 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来 1)探讨炎症皮肤中效应/记忆T细胞积聚的调控机制。 我们将通过在体内用CFSE标记皮肤T细胞来追踪反应性T细胞的迁移。 确定滞留在皮肤中的CFSE T细胞的趋化因子受体表达谱，与 那些继续通过皮肤迁移到引流淋巴的淋巴结；2)确定 外周组织效应/记忆T细胞抗原识别对其趋化因子受体表达的影响 以及它们在皮肤中的滞留与进入传入淋巴的迁移；3)试图颠覆 使用转基因T细胞和缺乏或缺乏趋化因子受体的小鼠的趋化因子受体反应性 过度表达趋化因子受体或趋化因子配体。这些研究的结果应该进一步 阐明调节T细胞在组织中转运的机制，并可能有助于治疗 大T细胞在周围组织中不适当地积聚的病理状态。

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.