Remodeling of lymph node-derived cytokine responses at the infected tissue site

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DESCRIPTION (provided by applicant): Compartmentalization of the immune response ensures tight regulation of T cell activation in the lymph node (LN) and precise effector T cell delivery and function at sites of inflammation. In the LN, naive helper (Th) CD4+ T cells acquire specialized functions and acquire distinct homing potential. Therefore both function and subsequent localization of effector cells appears to be pre-determined during differentiation in the LN. Our recent studies with the protozoa Leishmania major suggest that such tissue-specific accumulation of cytokine secreting effector cells can be subverted by a pathogen at the infected tissue site. L. major imposes a selective T cell cytokine response at the infected tissue site, independent of pathogen effects on LN priming of the repertoire. The early cytokine repertoire exiting the LN (a mixture of IL-4 and IFN3 producers) is modified at the infected tissue to operationally include IL-4 but not IFN3 producers. We hypothesize that L. major manipulates the immune response at the tissue site by subverting the accumulation or activity of leishmaniacidal, IFN3-producing, immune effectors. We have made three key observations that give us a novel handle on the regulation of responses at the infection site. Firstly, L. major inhibits the expression of Type 1 chemokines in the infected dermis, in part through direct action on the infected macrophage. Secondly, L. major induces the expression of two Type 2 chemokines, CCL1 and CCL7. Finally, local IL-4 production negatively regulates IFN3 production in the infected ear. Using a unique set of tools to track, in situ, an emerging immune response to L. major, this proposal seeks to identify key components of this early pathogen-host encounter that modulate the Th cytokine repertoire in the infected tissue. Specific Aim 1 will test a series of hypotheses accounting for changes in cytokine repertoire: differential recruitment/retention of immune effectors or entry into the tissue but subsequent functional modification. Specific Aim 2 will test the hypothesis is that L. major modulates the chemokine milieu resulting in the recruitment of IL-4 producers but not leishmaniacidal IFN3-producers. In turn, IL-4 production amplifies the restriction by compounding the selective chemokine milieu and/or directly inhibiting Th1 effector function. The concept of cytokine editing at the infected tissue site has important implications for immune therapy. Developing ways of harnessing a diverse LN repertoire to retune immune responses at the infection site, by manipulating the type of effectors recruited to the site, has great therapeutic potential for many disease states. PUBLIC HEALTH REVELANCE L. major imposes a selective T cell cytokine response at the infected tissue site, independent of pathogen effects on LN priming of the repertoire. Understanding pathogen-specific mechanisms of regulation at the tissue site therefore becomes key to the design of appropriate therapeutics. Developing ways of harnessing a diverse lymph node repertoire to retune immune responses at the infection site, by manipulating the type of effectors recruited to the site, has great therapeutic potential for many disease states.