Reovirus administered to the gut mucosal surface will be used to probe the roles of the cellular components of the murine gut associated lymphoid tissue (GALT) in preventing, limiting, containing, and resolving viral infections that commence via the intestinal route. Conventionally reared, germfree, neonatal, and severe combined immunodeficient (SCDD) mice will be used as hosts. Reoviruses are extremely effective at stimulating both mucosal B cell and specific cytotoxic (CD8) T cell responses. Thus, they provide model infections for defining the protective specific and non-specific cellular components that one should expect to be primed by an effective attenuated viral vaccine given orally. We will seek to establish any developmental interrelationship between precursor cytotoxic CD8+ lymphocytes (pCTLs) in Peyer's patches (PP) and the intraepithehal lymphocyte (IEL) compartment and to evaluate the persistence and turnover of specific pCTLS at both of these sites. We will investigate the roles of specific IELs at protecting vs. and limiting viral infection in the gut and whether GALT compartments such as PP and IEL are functionally linked via the homing receptors borne by their cellular constituents. The development and functional potential of subsets of specific CD4+ T cells in the different compartments of GALT will be examined by in vivo turnover studies using BrdU and in vitro microculture for both frequencies and ability to interact with B cells to promote the expression of particular Ig isotypes, such as IgA. Both specific CD8+ and CD4+ cells from GALT and systemic tissue will be further analyzed for fine specificities and in vivo function to address two unresolved concerns of practical significance: 1) whether virus processing and presentation by the gut route is substantially different than when it is introduced parenterally; and 2) whether the phenomenon of systemic tolerance and contrasuppression associated with oral immunization with some antigens extends to virus infections? Finally, using the SCID mouse as a model host that suffers fatal consequences of oral infection with reovirus due to liver failure, we will further attempt to clarify the role of natural killer (NK) cells acting in the IEL compartment or in the liver. Particularly, we will seek to define the bases for their accumulation in infected liver, target cell preferences, contributions to liver pathology, and interactions with adoptively transferred T cell subsets in vivo.
Showing the most recent 10 out of 33 publications
