Intracellular pathogens modify their host environment to survive in infected cells and evade adaptive immunity. Fundamental to understanding host-pathogen interactions is the need to define how T cells accumulate and interact with infected cells fro pathogen clearance. In many chronic infections, the pathogen and host responses may work in concert to limit protective immunity. We have gained new insight into the early infected microenvironment that might shape the magnitude or efficiency of a local protective Th1 response to Leishmania major. L. major actively downregulates the expression of a number of Th1-associated chemokines, particularly the CXCR3 chemokines and establishes a non-protective IL-4-domintated immune response in both susceptible and resistant strains. IL-4 itself also negatively regulates Th1 chemokines (CXCL9-11, CCL5) in inflamed/infected dermal tissue, effectively compounding the pathogen hold on the chemokine milieu. We speculate that CXCR3-chemokine cues for micro-anatomical positioning maybe critical for optimal Th1 localization within infected tissues and robust pathogen clearance. The efficacy of Th1 function at the infection site will therefore depend on the availability of these positioning cues. Thus, we hypothesize that L. major and host IL-4 limit the expression of key chemokines required for Th1 cells to position and function within the infected milieu. The goal is to determine how the local modulation of CXCR3-chemokines by L. major and IL-4 shapes the developing Th1 response in the infected tissue. This is achieved using cutting-edge IV-MPM tools through the following aims:
Specific Aim 1. Regulation of Th1 occupancy in the inflamed/infected dermis.
Specific Aim 2. Regulation of Th1 positioning within inflamed/infected tissues.
Specific Aim 3. Cellular targets of IL-4 in the regulation of CXCR3 ligand expression in inflamed tissue. This project will identify key pathways that promote or limit Th1 effector function within inflammatory sites. Defining the molecular events that impact effector T cell positioning in the tissues will be essential for the design of novel therapeutics that target chronic infection or co-infection by overriding the local tissue milieu.
This project will identify key pathways that promote or limit specific effector T cells within inflammatory sites. Identifying cellular and molecular components of effector T cell crosstalk and/or local cytokine dominance should also lead to new therapeutic targets that mitigate immune pathology and promote pathogen clearance and help us design more effective vaccines that minimize local competition between effector T cell subsets.
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