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

描述(由申请者提供)：通过建议的研究科学家发展奖，申请者将以她在T细胞迁移和免疫的抗原和趋化因子调节方面的先前经验为基础，利用皮肤炎症的活体模型来研究T细胞再循环。马萨诸塞州总医院安德鲁·D·卢斯特博士的实验室将提供一个刺激的环境，促进候选人的科学发展，实现她独立研究的最终目标。这项拟议的研究将为申请者提供机会来研究趋化因子在调节发炎皮肤中T细胞迁移命运方面的相互作用。 T细胞从血液进入组织和T细胞从组织进入传入淋巴都控制着淋巴细胞在外周部位的聚集及其参与免疫/炎症反应。几种单独的趋化因子在引导T细胞进入和离开皮肤的交通中的作用已经被表征。然而，不同的趋化因子信号之间在控制T细胞通过皮肤转运方面的相互作用仍然完全不清楚。这里，我们假设趋化因子进入、保留和退出信号的平衡调节效应/记忆T细胞在皮肤内的积累。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)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标记活体皮肤T细胞来跟踪反应性T细胞的迁移，并确定CFSE+T细胞与那些继续通过皮肤迁移到引流淋巴结的CFSE+T细胞的趋化因子受体表达谱；2)确定外周组织中效应/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向传入淋巴的迁移；3)尝试使用基因改变的T细胞和缺乏或过度表达趋化因子受体或趋化因子配体的小鼠来打破趋化因子受体反应性的平衡。这些研究的结果将进一步阐明调节T细胞在组织中转运的机制，并可能有助于治疗大量T细胞在周围组织中不当积聚的病理情况。

DESCRIPTION (provided by applicant): 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.