Generation of colonic T-cell mediated protective immunity after rectal infection with LCMV

Abstract

Abstract How viral-specific immunity is generated in the colon is not well understood, leaving a major gap in our knowledge of defining the parameters needed to develop vaccines against rectally transmitted pathogens. Clearance of most intracellular pathogens requires CD8 T cells, and since unlike the small intestine, the colon lacks organized lymphoid aggregates such as Peyer’s patches, generating protective immunity requires a series of orchestrated events to mobilize CD8 T cells to this mucosal organ. Complicating the generation of protective immunity is the fact that the colon naturally serves as an inductive site for tolerance against many commensal organisms and food antigens. Our central hypothesis, supported by our data, is that the tolerogenic nature of the colon limits induction of robust inflammatory responses needed to activate CD8 T cells for their efficient and timely recruitment to the colonic mucosa. We are using our newly established lymphocytic choriomeningitis virus (LCMV) rectal infection model to determine why CD8 T-cell priming is sub-optimal after rectal viral transmission of LCMV and why the activated CD8 T cells are unable to control the virus from spreading systemically. We are employing several genetic tools to ablate various monocytic and dendritic cell populations to determine their specific role in promoting CD8 T cell priming, activation, differentiation, and migration after rectal LCMV infection. This knowledge is required to break down barriers that have prevented development of successful T-cell-mediated vaccines against sexually transmitted RNA viruses, such as HIV, and will ultimately support the development of vaccines against sexually transmitted infections.