ABSTRACT CD8 + T lymphocytes often play a primary role in adaptive immunity to cytosolic microbial pathogens. Surprisingly, CD8 + T cells are not required for protective immunity to the enteric pathogen Shigella flexneri , despite the ability of Shigella to actively secrete proteins into the host cytoplasm, a location from which antigenic peptides are processed for presentation to CD8 + T cells. To determine why CD8 + T cells fail to play a role in adaptive immunity to S. flexneri , we investigated whether antigen-specific CD8 + T cells are primed during infection but are unable to confer protection or, alternatively, whether T cells fail to be primed. To test whether Shigella is capable of stimulating an antigen-specific CD8 + T-cell response, we created an S. flexneri strain that constitutively secretes a viral CD8 + T-cell epitope via the Shigella type III secretion system and characterized the CD8 + T-cell response to this strain both in mice and in cultured cells. Surprisingly, no T cells specific for the viral epitope were stimulated in mice infected with this strain, and cells infected with the recombinant strain were not targeted by epitope-specific T cells. Additionally, we found that the usually robust T-cell response to antigens artificially introduced into the cytoplasm of cultured cells was significantly reduced when the antigen-presenting cell was infected with Shigella . Collectively, these results suggest that antigen-specific CD8 + T cells are not primed during S. flexneri infection and, as a result, afford little protection to the host during primary or subsequent infection.