T cell migration within organized lymphoid tissue and within peripheral tissue is critical for the development and delivery of an organ specific immune response. This complex migratory behavior of T cells is essential for their function and is precisely controlled by the chemokine superfamily of chemotactic cytokines. This grant has funded our work on an important T cell chemokine receptor CXCR3 and its chemokine ligands IP-10 (CXCL10) and Mig (CXCL9). In prior funding periods, we generated unique reagents that allowed us to determine that CXCR3 and its ligands play important roles in T cell trafficking in peripheral tissue as well as in the reactive lymph node (LN). Many questions still remain though as to how CXCR3 and its ligands affect T cell interactions and accumulation in tissue. In this renewal application, we will continue with our tradition of generating novel reagents and utilizing cutting edge technologies to gain a deeper and more complete understanding of the in vivo functions of CXCR3 and its ligands. In the prior funding period, we found that despite IP-10 and Mig activating the same receptor, they have unique roles directing the migratory behavior of T cells in vivo. We hypothesize that differential expression determines their unique function in vivo, and this finely tuned cell-type specific pattern of ligand expression is required to deliver effector T cells to specific anatomic locations and govern their cellular interactions once in tissue. To study this, we will generate an IP- 10 and Mig reporter mouse to visualize the expression of these ligands in vivo. These reporter mice will be used in conjunction with the cutting edge technology of multiphoton intravital microscopy (MP-IVM) to elucidate the functional consequences of differential ligand expression and allow the direct study of CXCR3-dependent T cell migratory and interactive behavior in tissue. Using this revolutionary technique with our new reporter mouse, we will visualize for the first time the roles of CXCR3 and two of its ligands, IP-10 and Mig, in the migratory and interactive behavior of T cells in the reactive LN and in inflamed and infected peripheral tissue. Specifically we propose to: (1) To generate and validate an IP-10 and Mig reporter mouse strain to determine the pattern of CXCR3 ligand expression in vivo during the generation and delivery of an immune response;(2) To determine the role of CXCR3 and its ligands in regulating the interaction of T cells with dendritic cells in the reactive LN in vivo;(3) To determine the role of CXCR3 and its ligands in regulating the entry, interactions and retention of CD4+ T cells in a cutaneous model of inflammation in vivo;(4) To determine the role of CXCR3 and its ligands in regulating the entry and interactions of CD8+ T cells in the brain in a murine model of cerebral malaria in vivo. Studies supported by this grant have contributed to our understanding of IP-10 and CXCR3 and have established this chemokine system as an attractive candidate for modulating T cell trafficking in disease. The current proposal will extend and refine our knowledge of this important clinically relevant chemokine system.

Public Health Relevance

T cell recruitment to sites of inflammation and infection is a central component of the host immune response and is controlled by chemokines, which are chemotactic cytokines. Understanding how the chemokine superfamily regulates T cell trafficking will lead to novel therapies aimed at inhibiting a dysregulated immune response in autoimmune and allergic conditions as well as augmenting the host response to tumor cells, infectious agents and vaccines. This application proposes to continue our studies on the role of the chemokines IP-10 (CXCL10) and Mig (CXCL9) and their receptor CXCR3 in the control of T cell trafficking in the generation and delivery of an immune response.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cellular and Molecular Immunology - A Study Section (CMIA)
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Mccarthy, Susan A
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Massachusetts General Hospital
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