Multiple antigen-specific processing pathways for activating naive CD8(+) T cells in vivo

Current knowledge of the processing of viral Ags into MHC class I-associate d ligands is based almost completely on in vitro studies using nonprofessio nal APCs (pAPCs). This is two steps removed from real immune responses to p athogens and vaccines, in which pAPCs activate naive CD8+ T cells in vivo. Rational vaccine design requires answers to numerous questions surrounding the function of pAPCs in vivo, including their abilities to process and pre sent peptides derived from endogenous and exogenous viral Ags. In the prese nt study, we characterize the in vivo dependence of Ag presentation on the expression of TAP by testing the immunogenicity of model Ags synthesized by recombinant vaccinia viruses in TAP1(-/-) mice. We show that the efficienc y of TAP-independent presentation in vitro correlates with TAP-independent activation of naive T cells in vivo and provide the first in vivo evidence for proteolytic processing of antigenic peptides in the secretory pathway. There was, however, a clear exception to this correlation; although the pre sentation of the minimal SIINFEKL determinant from chicken egg OVA in vitro was strictly TAP dependent, it was presented in a TAP-independent manner i n vivo. In vivo presentation of the same peptide from a fusion protein reta ined its TAP dependence. These results show that determinant-specific proce ssing pathways exist in vivo for the generation of antiviral T cell respons es. We present additional findings that point to cross-priming as the likel y mechanism for these protein-specific differences.