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.
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