Program for Advanced Immune Bioimaging
In the past few decades we have made tremendous advances in our understanding of how immune responses are initiated in lymphoid tissues. We have gained knowledge of the lymph node (LN) architecture, spatial organization of cell types and how information is relayed from the infected tissue to the LN. Such information has helped to shape basic principles of pathogen recognition, the cues for differentiation of T and B cells into distinct effector cells and the induction of tissue-specific homing. However, basic knowledge of the fate of effector T cells once they leave the lymph node and enter inflamed/infected sites is far more limited. The objective of this Program Project is to bring together scientific expertise in leukocyte migration and effector function to address fundamental innate and adaptive effector processes in infected/inflamed tissues. 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 (APC) 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.
The research program headed by Deborah Fowell, Ph.D. is divided into four, interrelated components:
- Project 1 Leader, Minsoo Kim, Ph.D., Professor of Microbiology and Immunology. “Resolution of neutrophil response for effective T cell functions and tissue repair” Neutrophils are first responders in damaged or infected tissues. This influx is transient and is followed by neutrophil apoptosis and clearance by macrophages. The proposal identifies EGF as a key factor released by dying neutrophils in the influenza-infected lung.
- Project 2 Leader, Deborah Fowell, Ph.D., Professor of Microbiology and Immunology. “Spatial optimization of T cell activation at inflamed sites via cytokine/chemokine-dependent cellular clustering” The proposal reveals that at cutaneous sites of inflammation or infection, spatially restricted perivascular clusters (PVC) of chemokine producing cells arise that are enriched for APCs.
- Project 3 Leader, David J. Topham, Ph.D., Professor of Microbiology and Immunology. “Formation, Positioning, Motility, and Function of Tissue Resident Memory CD8+ T cells After Influenza Infection” The proposal identifies new subsets of TRM based on differential expression of CD49a and CD103 that express distinct transcriptional programs.
- Project 4 Leader, Patrick Oakes, Ph.D., Assistant Professor of Cell & Molecular Physiology “ Mechanics of T cell migration” The mechanics of how T cells navigate changing microenvironments within inflamed tissues is unclear. This proposal exploits differences in Th1 and Th2 migration to define critical physical parameters that optimize T cell ‘search’ of inflamed tissues.
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.