Mechanisms of resident memory T cell differentiation controlled by antigen recognition in non-lymphoid tissue

项目总结/摘要 组织驻留记忆CD 8 + T细胞现在已被证明在几乎每种类型的非淋巴细胞中形成并持续存在。 淋巴组织因为这些细胞永久地位于环境屏障表面， 在皮肤中，它们被认为对于宿主防御病原体至关重要。事实上， 记忆T细胞比记忆T细胞在循环中对各种病毒和 细菌感染用牛痘病毒（VacV）感染皮肤已经成为一种有吸引力的模型 询问控制高功能组织驻留T细胞形成的机制的系统 人口。我们最近已经证明，在组织微环境中抗原的局部识别， 对于非淋巴组织中的组织驻留记忆CD 8 + T细胞的形成至关重要。我们特别 结果表明，在效应CD 8 + T细胞进入VacV感染的皮肤后，第二次抗原接触导致快速的 CD 69的表达和这些T细胞在非淋巴组织中的保留。在本提案中，我们将 定义控制组织驻留记忆形成的分子和转录机制 在病毒感染期间，皮肤微环境中的CD 8 + T细胞作为基本免疫学， 在非淋巴组织中调节T细胞功能和记忆分化仍然在很大程度上不确定。到 为了解决这个问题，我们将1）确定T细胞受体对抗原的亲和力/亲合力如何塑造T细胞的表型， 2）确定Blimp 1/IL-10信号传导轴是否与组织驻留记忆T细胞区室的组成有关， 控制皮肤中组织驻留记忆T细胞的形成，以及3）识别相关抗原- 呈递细胞（造血和非造血），其通过呈递来调节组织驻留 肽和/或其他生存因子在病毒感染期间作用于皮肤中的CD 8 + T细胞。这个项目的总体目标是 项目将是确定调节组织驻留的形成和功能的机制， 记忆T细胞群，这将有助于我们改善疫苗设计的长期目标， 确定治疗皮肤炎性疾病的策略。

PROJECT SUMMARY/ABSTRACT Tissue-resident memory CD8+ T cells have now been shown to form and persist in nearly every type of non- lymphoid tissue. Because these cells are permanently positioned at environmental barrier surfaces such as the skin, they are believed to be critically important for host defense against pathogens. In fact, tissue-resident memory T cells are more protective than memory T cells in the circulation against a variety of viral and bacterial infections. Infection of the skin with Vaccinia virus (VacV) has emerged as an attractive model system to interrogate the mechanisms that control the formation of highly functional tissue-resident T cell populations. We have recently demonstrated that local recognition of antigen in the tissue microenvironment is critical for the formation of tissue-resident memory CD8+ T cells in non-lymphoid tissues. Specifically, we showed that after effector CD8+ T cells enter the VacV-infected skin, a second antigen encounter causes rapid expression of CD69 and retention of these T cells in the non-lymphoid tissue. In this proposal, we will now define the molecular and transcriptional mechanisms that control the formation of tissue-resident memory CD8+ T cells in the skin microenvironment during a viral infection, as the fundamental immunology that regulates T cell function and memory differentiation in non-lymphoid tissue remains largely undefined. To address this question, we will 1) determine how T cell receptor affinity/avidity for antigen shapes the composition of the tissue-resident memory T cell compartment, 2) determine if a Blimp1/IL-10 signaling axis controls the formation of tissue-resident memory T cells in the skin, and 3) identify the relevant antigen- presenting cells (both hematopoietic and non-hematopoietic) that regulate tissue-residency by presenting peptide and/or other survival factors to CD8+ T cells in the skin during viral infection. The overall goal of this project will be to define the mechanisms that regulate both the formation and function of tissue-resident memory T cell populations, which will contribute to our long-term goal of improving vaccine design and identifying strategies for the treatment of inflammatory disorders of the skin.