Cytolytic T cells are efficacious weapons of the immune system thought to counteract viral invasions by destroying infected cells before the assembly of viral progeny is completed. The antigen-specific receptor of T cells fails to recognize free virus, but binds to viral peptides presented by determinants of the major histocompatibility complex (MHC) on cell surfaces. Neurons, as opposed to most other cells lack expression of MHC determinants, thus offering a safe haven to neurotropic viruses. Nevertheless, some neuronal infections, such as with rabies virus, do not necessarily result in immunological ignorance and viral persistence but in an intracerebral (i.c.) immune response that presumably plays a key role in the outcome of the infection. the development of different parameters of T cell-associated immune responses to an acute neuronal infection with rabies virus will be studied in a mouse model comparing stimulation upon inoculation of a pathogenic, strictly neurotropic, rabies virus strain with that of an attenuated strain with a relaxed tropism. The ability of the attenuated strains to infect cells surrounding the site of viral entry presumably attracts the instant attention of the immune surveillance leading to activation of specific T cells as opposed to the virulent strains of rabies virus that are unlikely to induce a T cell response till a later stage of the infection when, upon multiplication in neuronal cell bodies, they lose their strictly neurotropic phenotype and then, upon centrifugal spread back into the periphery, infect cells other than neurons. The first part of this proposal will define the development of T cell-associated immune responses in the central nervous system (CNS) in correlation with the efficacy of spread of virulent compared to attenuated rabies virus. the i.c. inflammatory response will be dissected with regard to lymphocyte subsets, antibodies, lymphokines/cytokines, T cells (cytolytic T cells and T helper cells specific to rabies virus and bystander T cells activated to unrelated antigens) and putative upregulation of the expression of MHC determinants. the second part of this application is designed to elucidate the role of T versus B cells in protection, an issue that is still under debate, by adoptive transfer of naive or primed lymphocytes derived from immunocompetent mice into SCID mice infected with the pathogenic strain of rabies virus. the postulated long-term i.c. residence of specific T cells induced upon vaccination with an attenuated strain of rabies virus will be investigated by antibody (to CD4 and CD8) mediated depletion that should eliminate T cells residing in the periphery but not affect those hidden behind the blood brain barrier (BBB). Activated T cells have been shown to cross the BBB regardless of their specificity or the presence of foreign antigen in the CNS. Experiments described in the last part of this application will take advantage of this nonspecific migration by recruiting in vitro activated T cells to interact with infected neurons independent of expression of MHC determinants (not expressed on neurons unless induced by mediators such as interferon-gamma) using bispecific antibodies directed to the T cell receptor complex and the rabies virus glycoprotein.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Experimental Virology Study Section (EVR)
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Wistar Institute
United States
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