Chemokines regulate the traffick and function of various immune effector cells and play a critical role in host defense against a variety of intracellular pathogens. The CXC chemokine receptor 3 (CXCR3) is expressed on plasmacytoid dendritic cells, neutrophils, natural killer (NK) cells, and T cells. CXCR3 ligands (CXCR3Ls), particularly CXCL9 (Mig) and CXCL10 (IP-10) are produced in high levels during Leishmania infection but their role in mediating protective immunity against leishmaniasis is poorly defined. We have shown previously that CXCR3 plays a key role in mediating immunity against cutaneous L. major infection in resistant C57BL/6 mice by controlling recruitment of CD4+ and CD8+ T cells to the infected skin and IFN-? production within the lesion. We have also found that CXCR3 is expressed on a significant proportion of memory T cells and is required for their migration to the dermis after re-challenge. Our preliminary studies show that T cells from L. majorsusceptible BALB/c mice, but not resistant C57BL/6 mice, fail to up-regulate CXCR3 upon activation despite producing comparable levels of IFN-? as C57BL/6 T cells. Our recent study shows that distinct cytokinedependent mechanisms control the expression of CXCR3 on CD4+ and CD8+ T cells. We have also found that the B7 co-stimulatory pathway is involved in maintaining and regulating CXCR3 expression on T cells in L. major-resistant mice. These findings lead us to hypothesize that CXCR3 regulates host resistance against L. major by controlling parasite-specific effector and memory T cell responses and that BALB/c mice have a defect in up-regulating CXCR3 on T cells which contributes to their susceptibility to L. major. The goals of this proposal are to asses the role of CXCR3 in regulation of Leishmania-specific effector and memory T cell responses during L. major infection and to determine how CXCR3 expression is controlled on T cells.
(Aim 1) will examine the role of CXCR3 in regulation of antigen-specific effector CD4+ and CD8+ T cell responses during primary L. major infection in resistant C57BL/6 mice.
(Aim2) will determine the role of CXCR3 in the regulation of memory T cell recruitment and function during L. major infection in C57BL/6 mice.
(Aim 3) will determine the mechanisms by which the expression of CXCR3 is up-regulated on CD4+ and CD8+ T cells in C57BL/6 mice and will elucidate the cytokine pathways that are involved in preventing the induction of CXCR3 on T cells in susceptible BALB/c mice. In addition, we will determine whether CXCR3 levels can be manipulated in vivo by targeting these pathways in efforts to ameliorate infection in BALB/c mice. Finally, we will also study the role of B7:CD28 co-stimulatory pathway in CXCR3 regulation on T cells using specific pathway agonists and antagonists. These complementary approaches should provide insights into the role of CXCR3 in the regulation of antigen-specific effector and memory T cell responses during infection. These studies are important because they will not only enable us to optimize therapeutic and vaccine strategies against microbial infections by targeting chemokines and their receptors, but will eventually aid in designing immunotherapeutic approaches to treat autoimmune inflammatory diseases such as rheumatoid arthritis through blocking the recruitment of pathogenic T cells into the site of inflammation.
