Regulation of T cell migration by histamine

描述(由申请人提供)：T淋巴细胞在组织中的募集对健康和疾病中的局部免疫和炎症反应都是必不可少的。调节T淋巴细胞进入组织的机制还没有得到很好的描述。肥大细胞存在于所有组织中，是预制介质的丰富来源。其中最丰富的介质之一是组胺，它是在肥大细胞激活时通过抗原介导的激活或损伤而释放的。尽管组胺是生物学中研究最广泛的分子之一，但直到最近才发现它具有几种新的“免疫调节”特性，第四种受体是在2000年发现的。此外，现在有越来越多的证据表明，其他类型的细胞能够合成组胺，包括树突状细胞和中性粒细胞。我们已经取得了令人兴奋的发现，缺乏组胺的特定受体H1R的T细胞在过敏原攻击时无法迁移到肺中。缺乏H1R的小鼠也不会发生过敏性呼吸道疾病，但对T细胞衍生介质或当正常(H1R+)T细胞过继转移时反应正常。用H1R的选择性药理抑制剂治疗野生型小鼠也减少了过敏性呼吸道反应。根据我们的初步观察，我们假设肥大细胞释放组胺促进T细胞向组织中招募，T细胞上H1R的表达水平对此起调节作用。我们预测这些过程将在不同的组织中保守，组胺是T细胞介导的炎症和免疫的普遍调节因素。这些概念将通过使用体内和体外方法的三个特定目标来解决：特定目标1将测试组织驻留肥大细胞作为组胺来源的作用，并测试它们在过敏性呼吸道疾病中招募T淋巴细胞的能力。具体目标2将集中于H1R对T淋巴细胞的影响，并将研究H1R在T淋巴细胞亚群上的表达以及H1R在迁移和跨内皮运输中的功能参与(与Joan Cook-Mills博士合作)。具体目标3将使用迟发型超敏反应模型来研究组胺驱动的T淋巴细胞向皮肤募集的参与，并将检验组胺是T淋巴细胞被募集到组织中的普遍机制的假设。

DESCRIPTION (provided by applicant): The recruitment of T lymphocytes into tissues is essential for local immune and inflammatory responses in both health and disease. The mechanisms that regulate T lymphocyte trafficking into tissues are not well characterized. Mast cells are constitutively resident in all tissues and are a rich source of preformed mediators. One of the most abundant mediators is histamine which is release upon mast cell activation by antigen- mediated activation or to insult. Despite being one of the most extensively studied molecules in biology, histamine has only recently been found to have several novel "immunoregulatory" properties and a fourth receptor was discovered in 2000. In addition, there is now growing evidence that other cell types are capable of synthesizing histamine, including dendritic cells and neutrophils.We have made the exciting finding that T cells that lack a specific receptor for histamine, H1R, fail to migrate into the lung upon allergen challenge. Mice lacking H1R also fail to develop allergic airway disease but respond normally to T cell derived mediators or when normal (H1R+) T cells are adoptively transferred. Treatment of wildtype mice with selective pharmacological inhibitors of H1R also reduced allergic airway responses. Based on our preliminary observations, we hypothesize that mast cell release of histamine promotes the recruitment of T cells into tissues and that the expression levels of H1R on T cells serves to regulate this. We predict these processes will be conserved across different tissues and that histamine serves as a ubiquitous regulator of T cell mediated inflammation and immunity. These concepts will be addressed by three specific aims using both in vivo and in vitro approaches: Specific Aim 1 will test the role of tissue-resident mast cells as a source of histamine and test their ability to recruit T lymphocytes in allergic airway disease. Specific Aim 2 will focus on the influence of H1R on T lymphocytes and will investigate the expression of H1R on subsets of T lymphocytes and the functional involvement of H1R in migration and transendothelial trafficking (in collaboration with Dr Joan Cook-Mills). Specific Aim 3 will investigate the involvement of histamine-driven T lymphocyte recruitment to the skin, using models of delayed-type hypersensitivity, and will test the hypothesis that histamine is a ubiqitous mechanism by which T lymphocytes are recruited into tissues.