Role of focal CXCL10 in shaping Th1 micro-positioning and function in inflamed skin

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PROJECT SUMMARY/ABSTRACT Inflammatory cues within infected tissues are necessary for proper effector cell location and function. Spatial compartmentalization of T cells within lymph nodes (LNs) has recently been shown to promote T cell differentiation. Specifically, Th1 cell differentiation within LNs was shown to be dependent on CXCL10 (ligand for CXCR3, highly expressed on Th1 cells), as it served as a guiding cue for intra-nodal positioning and facilitated T cell:dendritic cell interactions during T cell priming. However, local cues that dictate effector T cell spatial location and function once T cells leave the LN and enter the tissue site of infection, are poorly understood. Using a reporter mouse for CXCL10 (REX3) and intra-vital multiphoton microscopy, we could, for the first time, determine the distribution of CXCL10 expressing cells at the site of inflammation in situ. We found a striking correlation between dense clusters of CXCL10 producers and the accumulation of Th1 cells. In addition, Th1 cells decelerated within the dense CXCL10-clusters. We hypothesize that the spatially restricted expression of CXCL10 is critical for the proper localization and function of Th1 cells within the inflamed/infected milieu. In many chronic infections, protective immunity is limited due to pathogen-induced modifications to the host micro-environment. Indeed, T cells have been shown to have limited access to dense areas of Leishmania major (L.major) and Toxoplasma Gondii infected cells in infected tissues. Our group previously showed that L.major can actively down regulate CXCL10 in infected macrophages, the predominant infected cell in the dermis. We hypothesize that by limiting CXCL10 expression in infected cells, L.major interferes with the proper localization and function of Th1 cells that are required for efficient pathogen clearance. The overall goal is to define basic mechanisms that influence Th1 positioning and/or function within specific micro-anatomical regions rich in CXCL10 in the inflamed milieu, and to determine the effect of CXCL10 availability on the ability of Th1 cells to locate and clear a pathogen. Aim 1. Determine the role of CXCL10 in shaping T cell motility and function within the inflamed tissue Aim 2. Can enhancing CXCL10 availability impact T cell positioning and boost immunity against L.major? Understanding the fundamental cues for Th1 localization, motility and function within infected tissues may be critical for the development of adjuvants that suitably enhance the adaptive immune response to vaccine antigens and to develop therapeutic approaches that optimize responses to chronic inflammation.