The maintenance of homeostatic immune surveillance and the development of effective immune responses require that leukocytes cross tissue barriers and move throughout the body, migrating in and out of the bone marrow, lymphoid and non-lymphoid tissues, under both normal and infected or inflamed conditions. The efficient trafficking of activated effector T cells into peripheral non-lymphoid tissues is key to enact their protective functions. Insufficient T cell activity contributes to impaired local adaptive immunity, recurrent infections and delayed wound healing, whereas excessive T cell recruitment leads to an exaggerated inflammatory response and the associated tissue damage. Despite considerable advances in the understanding of T cell trafficking in secondary lymphoid organs, the real-time recruitment of T cells into inflamed tissues is not well characterized. Successful early local innate immune response is critical for elicitation of T cell effector functions at the peripheral tissue sites. Therefore, it is likely that the type of innate cells, mode of early innate responses, and associated local inflammatory mediators will all impact on the molecular mechanisms by which effector T cells successfully move into the inflamed tissues. Our preliminary data showed that migrating neutrophils leave membrane trails into the influenza-infected trachea. The trail contains high level of chemokine CXCL12, which enhances effector CD8 T cell migration. In this study, we hypothesize that the diversity in the local tissue milieus created by the early innate responses provides a combinatorial mechanism for generating both specificity and flexibility in T cell-endothelial cell interactions and transmigration in vivo. We will investigate;(1) whether the neutrophil trails provide highly localized haptotactic chemical signals to guide the subsequent recruitment of effector T cells? (2) if signals from the neutrophil trails influence local inflammatory chemokines and regulate the tissue-specific homing of effector T cells, and (3) the effects of the local inflammatory cytokine TNF-a on integrin activation in effector T cells and their migration. Understanding how to control effector T cell homing through the manipulation of local tissue environments has potential applications in many chronic inflammatory settings.

Public Health Relevance

T cells are abundantly present in the sites of autoimmune disease and chronic inflammation, where they produce a wide array of cytokines that can exert pro-inflammatory effects. Therefore, recruitment of T cells to the inflammation sites has emerged as a key factor in the pathogenesis of the inflammatory diseases. This study will determine the molecular mechanisms that regulate T cell migration, which would lead to the design of a novel therapeutic approach to treat the chronic inflammatory disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1-LGR-I (J1))
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University of Rochester
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