Mucosal memory CD 8 + T cells are selected in the periphery by an MHC class I molecule

A hallmark of immune memory is that repeated infections are met with accelerated and enhanced protective immunity1. Furthermore, unlike naive T lymphocytes or central memory T cells, which reside in lymphoid tissues, some antigen-experienced T cells gain the ability to persist long term as effector memory T cells (TEM cells) in nonlymphoid tissues such as the intestine2–5. Central memory T cells, which respond with robust clonal expansion, are effective at protecting against infections by pathogens that replicate systemically6, but they are probably inadequate to prevent the transmission of viruses (including human immunodeficiency virus (HIV)) or intracellular bacteria that penetrate the mucosal epithelia3,7. Effective resistance to the transmission of such pathogens requires the presence of local, antigen-specific TEM cells before rechallenge7. Therefore, strategies aimed at inducing a powerful protective immune response that also warrants the formation of preexisting mucosal antigen-specific TEM cells are considered an essential goal of successful vaccination. Listeria monocytogenes, a Gram-positive intracellular pathogen of human and other mammals, including mice, is a food-borne pathogen; after ingestion and uptake by phagocytic cells, such as monocytes and dendritic cells (DCs), L. monocytogenes disseminate from the intestine into the bloodstream and spread to various systemic tissues such as the liver8. In humans, ingested L. monocytogenes may cause listeriosis because of its ability to also infect nonphagocytic cells, such as intestinal epithelial cells, through interaction of internalin (expressed by L. monocytogenes) and human E-cadherin (expressed on the basolateral pole of the enterocytes)9. In contrast, mice infected orally with L. monocytogenes do not develop listeriosis because of the inability of internalin to interact with mouse E-cadherin. Instead, mice clear the ingested bacteria via an effective CD8-dependent protective immune response, although bacteria that cross the mucosal barrier can spread to the liver and other organs via the blood, as can happen in humans8. Such observations have important implications for immunization strategies and indicate that the presence of local preexisting mucosal immunity might be key for the induction of effective protective immunity to ingested pathogens. Despite that, however, most knowledge of immune memory has been gained from model systems that use systemic immunization routes and memory generation in lymphoid tissues. Such preexisting immunity might be highly effective in combating systemic infection but is probably inadequate for controlling pathogens that invade the body via the oral route. Because of the protective mucosal CD8-mediated anti– L. monocytogenes response in mice and because of the emergence of genetically manipulated avirulent, attenuated strains of wild-type and recombinant L. monocytogenes deficient in ActA protein (which is essential for the motility and spreading of L. monocytogenes; ActA− L. monocytogenes) as important vectors for vaccination8,10,11, immunization of mice with L. monocytogenes introduced via the oral route represents an optimal approach with which to examine the mechanisms and conditions that lead to the generation of preexisting mucosal immune memory. Homodimers of CD8 (CD8αα) induced on activated CD8αβ+ T cells, which maintain expression of CD8αβ, mark those primary effector cells that have a propensity to differentiate into memory cells12. In mice, the epithelium of the intestine is greatly enriched for memory CD8αβ+ T cells