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Mechanisms of CD49a Expression and Resident Memory T Cell Formation in Skin.

皮肤中 CD49a 表达和常驻记忆 T 细胞形成的机制。

基本信息

批准号：
9302659
负责人：
SHANNON K BROMLEY
金额：
$ 41.69万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-23 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9302659
关键词：
Acute Address Adhesions Adhesives Affect Allergic Disease Anti-Bacterial Agents Antigens Atopic Dermatitis Autoimmune Diseases Autoimmune Process Autoimmune Responses Bacterial Genes Basement membrane Biology CD8-Positive T-Lymphocytes CD8B1 gene Cells Collagen Collagen Receptors Cutaneous Data Dermis Development Disease E-Cadherin Environment Epidermis Epithelial Cells Extracellular Matrix Focal Infection Goals Health Herpesvirus 1 Host Defense Human Immune Immune Targeting Immune response Immune system In Situ Individual Infection Infectious Agent Inflammation Inflammatory Integrins Interleukin-4 Link Maintenance Mediating Memory Modeling Molecular Morphology Mus Organ Pathway interactions Peripheral Play Population Predisposition Recruitment Activity Recurrence Regulation Signal Transduction Simplexvirus Site Skin T memory cell T-Lymphocyte Testing Therapeutic Therapeutic Uses Tissues Transforming Growth Factor beta Vaccine Design Vaccines Viral Vitiligo adhesion receptor antigen challenge autoreactivity base cell motility clinical application cytokine integrin alpha1beta1 interstitial interstitial cell melanocyte migration mouse model novel novel therapeutics pathogen prevent receptor receptor expression response skin disorder targeted treatment

项目摘要

The immune system must defend the host at the most likely sites of pathogen encounter--the epithelial cell boundaries between barrier organs and the host's environment. Exciting recent data demonstrate that a population of memory T cells (TRM) resides long-term within peripheral tissues and provides a first line of host defense from pathogens that cause local infection. However, in some settings, the local persistence of memory T cells that provide robust response is detrimental. TRM are thought to play a key role in local, recurring inflammatory skin diseases. This proposal seeks to address significant gaps in our understanding of the mechanisms that regulate cutaneous TRM in health and disease. Defining mechanisms that control TRM precursor localization and persistence within skin will be important for optimizing vaccines to provide local protection as well as therapies to prevent unwanted inflammation. Mechanisms that direct the interstitial migration, persistence and response of cutaneous TRM will be defined in a normal immune response to HSV infection and in autoimmune vitiligo. While the local cytokine microenvironment is known to direct TRM formation, factors that inhibit TRM differentiation/persistence are unknown. This proposal will investigate the hypothesis that depending on the cytokine microenvironment TRM formation is either promoted or inhibited. Lastly, although TRM have been identified at sites of cutaneous inflammatory disease, targeting TRM is an untested therapeutic approach. We will use a mouse model of vitiligo with clinical application to investigate the novel hypothesis that autoreactive TRM maintain depigmentation, and that depletion of autoreactive TRM will prevent and/or ameliorate disease. Up-regulating pathways that promote the persistence of T cells in peripheral tissues is a critical focus of current vaccine design; it may be equally important to create approaches that reverse these pathways to prevent unwanted TRM accumulation within inflamed tissues.

免疫系统必须在最有可能遇到病原体的地方--上皮细胞--保护宿主。屏障器官和宿主环境之间的边界。最近令人兴奋的数据表明，记忆T细胞群(TRM)长期驻留在外周组织中，并提供第一宿主防御引起局部感染的病原体。然而，在某些设置中，内存的本地持久性提供强健反应的T细胞是有害的。TRM被认为在局部、复发的炎症性皮肤病。这项建议旨在解决我们对在健康和疾病中调节皮肤TRM的机制。定义控制TRM的机制前体在皮肤内的定位和持久性对于优化疫苗以提供局部保护和治疗，以防止不必要的炎症。引导组织间隙的机制皮肤TRM的迁移、持久性和反应将被定义为对HSV的正常免疫反应感染和自身免疫性白癜风。而已知的局部细胞因子微环境指导着TRM 形成，抑制TRM分化/持久性的因素尚不清楚。这项提案将调查根据细胞因子微环境的不同，TRM的形成要么被促进，要么被抑制。最后，尽管已经在皮肤炎性疾病部位发现了TRM，但靶向TRM是一种未经测试的治疗方法。我们将使用具有临床应用的白癜风小鼠模型来研究新的假设认为，自身反应性TRM维持色素脱失，而自身反应性TRM的耗尽将预防和/或改善疾病。上调促进T细胞在体内持续存在的途径外周组织是当前疫苗设计的一个关键焦点；创造方法可能同样重要逆转这些途径，以防止不必要的TRM在炎症组织中积聚。