MHC class Ib molecules are members of a diverse family of non-polymorphic proteins that present bacterial peptides to cytolytic T lymphocytes (CTL). The murine H2-M3 molecule is an MHC class Ib molecule that binds short, hydrophobic peptides that contain N-formyl methionine at the amino terminus. Murine infection with Listeria monocytogenes, an intracellular bacterium, elicits CTL that recognize bacterial N-formylated peptides complexed with the H2-M3 MHC class Ib molecule. To enable direct identification of H2-M3 restricted T cells during bacterial infection, tetrameric H2-M3 molecules were complexed with one of the N-formylated L. monocytogenes peptides. These studies demonstrated that H2-M3 restricted T cell responses following primary infection occur more rapidly than H2-KDa restricted T cell responses. H2-M3 restricted T cells are cytolytic and secrete gamma-interferon, suggesting they play an important role in bacterial clearance. Interestingly, H2-M3 restricted memory T cell responses are attenuated compared to H2-KDa restricted responses. The specific aims of this application are: 1) To characterize H2-M3 restricted CTL responses in liver and gut of orally infected mice, providing insights into the role of MHC class Ib restricted T cells responses at a mucosal site following the natural route of L. monocytogenes infection; 2) To determine the mechanisms responsible for accelerated H2-M3 restricted T cell responses during primary infection with L. monocytogenes; and 3) To investigate the basis for attenuated H2-M3 restricted memory T cell responses in mice reinfected with L. monocytogenes. The studies proposed in this application will provide an unprecedented view of MHC class Ib restricted T cell responses to bacterial infection and will test the hypotheses that H2-M3 restricted T cells play a prominent role in intestinal immunity and that intestinal bacterial flora can influence pathogen specific T cell repertoires. Additionally, these experiments may provide novel insights into the factors driving in vivo T cell expansion and memory generation.

R01AI049602

2000-08-15

2006-05-31