Mast cell control of endogenous, antigen-specific CD4 T cell immunity

 描述（由申请人提供）：长期以来已知肥大细胞是哮喘和过敏的重要细胞原因。最近的研究挑战了这种病理生理学范式，支持肥大细胞在免疫的各个方面发挥更加多样化的作用。在文献中的确认报告已经基于肥大细胞如何被刺激而将效应子和抑制子的作用分配给肥大细胞。虽然很明显肥大细胞是早期清除病原体（如细菌和寄生虫）所必需的有效先天免疫细胞，但对肥大细胞在适应性免疫中的作用，特别是其对辅助T细胞免疫的作用知之甚少。我们的初步实验使用主要组织相容性复合物II类（MHCII）四聚体检查肥大细胞对内源性，抗原特异性辅助CD4 T细胞免疫的影响表明，诱导肥大细胞脱粒的组织导致显着增加抗原特异性辅助CD4 T细胞数量在引流淋巴结。此外，我们确定了肥大细胞的缺乏导致含抗原组织中抗原特异性CD4 T细胞积累的显著减少。这些综合的结果，除了我们过去的工作，使我们的假设，肥大细胞有助于内源性辅助T细胞群体的扩增和迁移，并最终调节辅助T细胞的功能表型。我们进一步证实，这种T细胞活化是通过直接肥大细胞介导的。 细胞对CD4 T细胞的影响，包括肥大细胞产生的细胞因子，这是由肥大细胞最初如何活化决定的。我们将使用MHCII四聚体来分析内源性抗原特异性CD4 T细胞与肥大细胞缺陷型小鼠或用骨髓来源的肥大细胞重建的肥大细胞缺陷型小鼠的组合来检验这一假设。目的1将研究肥大细胞在启动和维持抗原特异性CD4 T细胞活化中的作用。 Aim 2将评估肥大细胞响应于不同肥大细胞活化刺激而驱动CD4 T细胞Th表型的功能。这些研究旨在检查多种肥大细胞对抗原特异性CD4辅助T细胞免疫的影响。这项研究应该提供新的机会，以指导有利于病原体消除的反应，从而更好地基于肥大细胞的治疗干预，有益于人类健康。

 DESCRIPTION (provided by applicant): Mast cells have long been known to be important cellular causes of asthma and allergy. Recent studies have challenged that pathophysiological paradigm in favor of a much more diverse role for mast cells in various aspects of immunity. Conflicting reports in the literature have assigned both effector and suppressor roles to mast cells based on how they are stimulated. While it is clear that mast cells are potent innate immune cells essential for early clearance of pathogens, such as bacteria and parasites, far less is known about what role mast cells play in adaptive immunity, especially with respect to their effect on helper T cell immunity. Our preliminary experiments using major histocompatibility complex class II (MHCII) tetramers to examine mast cell effects on endogenous, antigen-specific helper CD4 T cell immunity showed that inducing mast cell degranulation in the tissue led to a significant increase in antigen-specific helper CD4 T cell numbers in draining lymph nodes. Further, we established that a lack of mast cells led to a marked decrease in antigen-specific CD4 T cell accumulation in antigen-containing tissue. These combined results, in addition to our past work, lead us to the hypothesis that mast cells contribute to endogenous helper T cell population expansion and migration and, ultimately, regulate helper T cell functional phenotypes. We further posit that this T cell activation is mediated through direct mast cell effects on CD4 T cells, including cytokine production by mast cells and that this is determined by how mast cells are initially activated. We will test this hypothesis using MHCII tetramers to analyze endogenous, antigen-specific CD4 T cells combined with mast cell deficient mice or mast cell deficient mice reconstituted with bone marrow derived mast cells. Aim 1 will examine the role for mast cells in initiating and maintaining the antigen-specific CD4 T cell response in antigen-containing tissue and antigen-draining lymph nodes while Aim 2 will assess the function of mast cells in driving CD4 T cell Th phenotypes in response to different mast cell activation stimuli. These studies are designed to examine multiple mast cell effects on antigen-specific CD4 helper T cell immunity. This investigation should provide novel opportunities to guide the response in favor of pathogen elimination leading to better mast cell based therapeutic interventions benefitting human health.