The host response against microbial pathogens consists of the integrated actions of both the innate and adaptive immune systems. Protective immunity to viruses is dependent upon the complex interactions between cytokines and chemokines to regulate both innate and adaptive effector functions. It has been shown that the cytokines induced by pathogens may determine the cellular components that get activated by inducing specific chemokines in infected tissue compartments. T lymphocyte activation, particularly CD8+ T cells, are required to limit virus-associated tissue damage and the promotion of viral clearance from MCMV-infected tissues. The protective function of CD8+T cells against MCMV activation is well documented and consists of the production of IFN-? and TNF-? during late acute infection. However the role CD8 T lymphocytes play when they are recruited to sites of infection has not been assessed. It has been shown that MCMV induces the production of the chemokines CXCL9 and CXCL10, two known CXCR3 ligands, in the liver. These are key factors in promoting the recruitment of CD8+ T cells to sites of MCMV in the liver. CXCR3 is expressed on the surface of CD8+ T cells and a subset of MCMV- specific CD8+ T cells accumulating in the liver during infection. This proposal seeks to determine the significance of CXCL9 and/or CXCL10, in promoting the effector functions of CD8+ T cells during MCMV infection and to investigate the mechanism by which these chemokines modulate the effector functions of CD8 T lymphocytes. We will make use of proliferation and cytoxicity assays to evaluate the effects of CD8+ T cells. ELISAs and flow cytometry analysis will be used to measure ex vivo cytokine and chemokine production. We already have Mig-/-, IP10 -/- and CXCR3 -/- pups that are ready to be used. The results obtained will contribute to the understanding of events that are important for defense of viral infection and will help to define a critical cascade for protection during infection. It will also help to elucidate the chemokine/ chemokine receptor functions in the recruitment of lymphocytes responding to a virus infection in tissue sites.
