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

描述（由申请人提供）：通过拟议的研究科学家发展奖，申请人将利用其先前在T细胞迁移和免疫的抗原和趋化因子调节方面的经验，使用皮肤炎症的体内模型研究T细胞再循环。Andrew D.马萨诸塞州总医院的医学博士，博士将提供一个刺激的环境，以进一步促进候选人的科学发展，实现她独立调查的最终目标。拟议的研究将为申请人提供机会，以检查趋化因子在调节炎症皮肤中T细胞迁移命运中的相互作用。 T细胞从血流进入组织和T细胞从组织离开进入传入淋巴都控制淋巴细胞在外周部位的积累及其参与免疫/炎症反应。几个单独的趋化因子在指导T细胞进入和离开皮肤的交通中的作用已经被表征。然而，不同趋化因子信号在控制T细胞通过皮肤的转运中的相互作用仍然完全未知。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在体内标记皮肤T细胞来跟踪应答T细胞的迁移，并确定保留在皮肤中的CFSE+ T细胞与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）确定效应器的后果/外周组织中的记忆T细胞抗原识别对其趋化因子受体表达的影响及其在皮肤中的保留与迁移到传入淋巴中的关系; 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推翻趋化因子受体反应性的平衡。这些研究的结果应进一步阐明调节T细胞通过组织转运的机制，并可能有利于治疗大T细胞浸润在外周组织中不适当积累的病理条件。

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.