Granzyme A-secreting T cells in allergic inflammation

 描述（由申请人提供）：T辅助细胞通过响应细胞因子环境并分化成具有专门功能的效应细胞来协调各种类型的炎症。许多特化功能由分泌的细胞因子赋予，但包括为迁移和效应子功能提供特异性的额外基因的表达。为了增加T辅助细胞对环境的反应能力的复杂性，Th细胞可以整合来自多种细胞因子的信号以产生不同的表型。例如，在过敏性炎症的情况下，IL-4促进产生IL-4和IL-13的Th 2细胞的发育，尽管IL-4与TGF β组合促进主要分泌IL- 9的Th 9细胞的发育。IL-6是在许多炎性疾病中检测到的另一种细胞因子，包括过敏性炎症，其可以刺激急性反应，并促进Th细胞分化为T滤泡辅助细胞表型， 或与TGF β组合，对分泌IL-17的Th 17亚群。在体内，在过敏性环境中引发的CD 4 T细胞可能遇到IL-4、IL-6和TGF β，这些信号的整合导致疾病的细胞表型谱。我们最近发现，在IL-4和IL-6存在下体外培养的CD 4 T细胞形成独特的分化特征，其特征在于表达丝氨酸蛋白酶颗粒酶A（GrA）的细胞比例大幅增加，所述丝氨酸蛋白酶颗粒酶A在功能上与自身免疫性疾病有关。GrA+细胞缺乏其他谱系特异性细胞因子的共表达，这表明这些细胞可能代表T辅助细胞的一个独特子集。我们进一步表明，GrA mRNA在易患特应性皮炎的小鼠皮肤中表达，并且与同窝对照相比，这些小鼠外周GrA+ CD 4 T细胞的频率升高。本申请的目的是确定GrA是否有助于过敏性炎症，并定义GrA+ CD 4 T细胞的功能和来源。我们假设表达GrA的T细胞促进过敏性炎症。我们将使用缺乏或具有GrA异位表达的T细胞的小鼠模型中的方法来测试这一假设，以检查这些细胞在多种模型中的功能。我们将进一步定义Th细胞如何整合建立GrA分泌表型所需的STAT 3和STAT 6信号。这些研究将确定一种新型细胞类型在过敏性疾病中的功能，并确定治疗干预的潜在靶点，这些靶点可以减轻过敏性疾病患者的症状并改善其生活质量。

 DESCRIPTION (provided by applicant): T helper cells coordinate various types of inflammation by responding to the cytokine environment and differentiating into effector cells that have specialized functions. Many of the specialized functions are conferred by cytokines secreted, but include the expression of additional genes that provide specificity for migration and effector function. To add complexity to the ability of T helper cells to respond to the environment, Th cells can integrate signals from multiple cytokines to generate distinct phenotypes. For example, in the context of allergic inflammation, IL-4 promotes the development of Th2 cells that produce IL-4 and IL-13, although IL-4 in combination with TGFb promotes the development of Th9 cells that predominantly secrete IL- 9. IL-6 is another cytokine detected in many inflammatory diseases, including allergic inflammation that can stimulate acute responses, and promote differentiation of Th cells to the T follicular helper cell phenotype, or, in combination with TGFb, to the IL-17-secreting Th17 subset. In vivo, it is likely that CD4 T cells primed in an allergic environment encounter IL-4, IL-6 and TGFb, and the integration of these signals results in a spectrum of cellular phenotypes that contributes to disease. We have recently identified that CD4 T cells cultured in vitro in the presence of IL-4 and IL-6 develop a unique differentiation profile characterized by a large increase in the proportion of cells that express the serine protease granzyme A (GrA) that has been functionally implicated in autoimmune disease. GrA+ cells lack co-expression of other lineage-specific cytokines, suggesting that these cells may represent a distinct subset of T helper cells. We further show that GrA mRNA is expressed in the skin of mice that are prone to atopic dermatitis and that these same mice have elevated frequencies of peripheral GrA+ CD4 T cells as compared to littermate controls. The goal of this application is to determine if GrA contributes to allergic inflammation, and define the function and derivation of GrA+ CD4 T cells. We hypothesize that GrA-expressing T cells promote allergic inflammation. We will test this hypothesis using approaches in mouse models with T cells that lack or have ectopic expression of GrA to examine the function of these cells in multiple models. We will further define how the Th cell integrates the STAT3 and STAT6 signals required for establishing the GrA-secreting phenotype. These studies will define the function of a novel cell type in allergic disease, and identify potential targets for therapeutic intervention that could reduce symptoms and improve the quality of life of patients suffering from allergic disease.