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.
| Ploss, Alexander; Tran, An; Menet, Ewa et al. (2005) Cross-recognition of N-formylmethionine peptides is a general characteristic of H2-M3-restricted CD8+ T cells. Infect Immun 73:4423-6 |
| Ploss, Alexander; Leiner, Ingrid; Pamer, Eric G (2005) Distinct regulation of H2-M3-restricted memory T cell responses in lymph node and spleen. J Immunol 175:5998-6005 |
| Ploss, Alexander; Lauvau, Gregoire; Contos, Brian et al. (2003) Promiscuity of MHC class Ib-restricted T cell responses. J Immunol 171:5948-55 |
| Kerksiek, Kristen M; Ploss, Alexander; Leiner, Ingrid et al. (2003) H2-M3-restricted memory T cells: persistence and activation without expansion. J Immunol 170:1862-9 |
