? OVERALL Pathogen infection initiates local inflammation that leads to the influx of innate effector cells and elaboration of chemokines, cytokines and other soluble mediators. T effector cells entering the infected tissue encounter a tissue environment that has been differentially altered from the basal state depending on the type of pathogen and corresponding innate inflammatory response. Effector T cells must migrate through this interstitial space to locate antigen-presenting cells and infected target cells and receive activation signals for effector function, pathogen clearance and establishment of tissue memory. Although the framework of these complex interactions between innate cells, soluble mediators and tissue architecture is established, the ability of effector T cells to sense and interpret different inflammatory environments and the impact on immune function are poorly understood. Yet, it is within the infected peripheral tissues that they must execute their effector function for pathogen clearance. It is also within peripheral tissues where dysregulated inflammation leads to immune pathology; from autoimmune to cardio-vascular disease. Using innovative tools for in situ modulation and visualization of immune responses in the skin and lung of the mouse the goal of this Program Project is to gain insight into the signals that control T cell recruitment, migration and activation in infected or inflamed tissues of the skin and lung. The previous funding cycle has identified new mechanisms of T cell recruitment, interstitial migration, and positioning of effector and tissue memory subsets. This proposal builds on these molecular checkpoints at sites of inflammation to determine how external signals from innate cells and the tissue microenvironment shape the position and function of effector T cells for protective immunity. Project 1. Resolution of neutrophil response for effective T cell functions and tissue repair. Dr Minsoo Kim. Hypothesis: that neutrophil death is not passive, but rather, that the release of specific factors from dying neutrophils promotes effective T cell activation and tissue repair. Project 2. Spatial optimization of T cell activation at inflamed sites via cytokine/chemokine-dependent cellular clustering. Dr Deborah Fowell. Hypothesis: that peripheral T cell activation occurs in chemokine-rich peri-vascular clusters that nucleate and amplify T cell recruitment/activation for efficient pathogen clearance. Project 3. Formation, Positioning, Motility, and Function of Tissue Resident Memory CD8+ T cells After Influenza Infection. Dr David Topham. Hypothesis: specific TRM subsets occupy distinct spatial microenvironments in the airway that confer functional differences in protection against influenza infection. Project 4. Mechanics of T cell migration. Dr Patrick Oakes. Hypothesis: that migration of different immune cells lies along a single continuum, differing only in relative contributions of adhesion and force generation. Core A. Administrative, Fowell D.J.; Core B. Imaging, Kim M.; Core C. Reagents, Miller J.
- OVERALL The successful completion of the studies will identify key events in immune function at inflamed sites that could serve as inflammation-specific therapeutic targets to mitigate destructive inflammation and promote protective responses to infection.
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