The role of CCL3 and its receptors in protective anti-viral immunity

The development of successful anti-viral immunity relies on the induction of virus-specific memory cells. Upon re-exposure to virus, the virus-specific memory cells enable the development of a protective secondary immune response resulting in rapid viral clearance. Despite its clinical significance, the mechanisms responsible for generating protective immunity are poorly understood. I studied the protective anti-viral T cell responses using lymphocytic choriomeningitis virus (LCMV) infection of mice as a model system. In order for T cells to eliminate LCMV, virus-specific T cells must expand, traffic to the site of viral infection, and perform their effector function facilitating rapid viral clearance. The chemokine CCL3 (macrophage inflammatory protein-1 alpha or MIP-1α) has been implicated to impact all of these facets of T cell responses. CCL3 has been shown to induce chemotaxis of T cells in vitro, and to augment T cell proliferation and T cell cytolytic activity in vitro. I have used mice lacking CCL3 or its receptors CCR1 and CCR5 to study the role of these molecules in the immune response against LCMV infection.; My research demonstrates that CCL3, CCR1, and CCR5 are crucial for rapid elimination of LCMV after re-infection within the CNS. This failure to develop protective immunity is not due to impaired generation, trafficking, or maintenance of virus-specific T cells. Furthermore, diminished cytolytic activity or decreased production of the anti-viral cytokine IFN-γ is not responsible for the inability of chemokine and chemokine receptor deficient mice to develop protective immunity. Additionally, cell transfer experiments indicated that CCL3 produced by non-splenocytes is essential for the development of protective immunity. Given these results, I speculate that CCL3 produced in the microenvironment of the brain following LCMV infection is essential for the effector function of T cells within the CNS which facilitates efficient virus control. These studies highlight the importance of CCL3 and its receptors CCR1 and CCR5 in the generation of protective immunity. It is likely that vaccines designed to induce production of CCL3 would be more effective in generating protective anti-viral immune responses.