Bacterial protein synthesis initiates with N-formyl methionine, which is distinct from the great majority of eukaryotic proteins synthesis, which initiates with methionine. The mammalian immune system has evolved several mechanisms to recognize bacterial formyl-methionine peptides following bacterial infection. For example, many inflammatory cells express a chemotactic receptor called FPR (for formyl peptide receptor) that binds short, hydrophobic peptides that contain N-formyl methionine.
Another receptor for bacterial peptides is H2-M3, an MHC class Ib molecule that selectively binds peptides that contain N-formyl methionine at the amino terminus. H2-M3 presents Listeria monocytogenes derived peptides to CD8 T cells during murine infection.
We have shown that the H2-M3 restricted CD8 T cell response is very rapid and robust in most mouse strains, and that the kinetics of the primary response correlates with bacterial clearance. Surprisingly, the memory response to H2-M3 restricted peptides is quite small in comparison to H2-Kd restricted responses. This finding suggests that the capacity of H2-M3 and H2-Kd restricted T cells to undergo in vivo expansion differs. The reasons for this disparity are currently under investigation in our laboratory.
We have obtained mice that express the T cell receptor transgenes specific for a Listeria monocytogenes derived, H2-M3 restricted epitope. These mice provide a useful system to characterize the in vivo activation and expansion of H2-M3 restricted T cells in infected mice. We are using adoptive transfer of CFSE-labeled TCR transgenic T cells into recipient mice to characterize the proliferation of H2-M3 restricted T cells in mice during primary and secondary infection with L. monocytogenes. In vitro studies are also being performed to characterize intrinsic differences between CD8 T cells that are restricted by H2-M3 versus H2-Kd.
As mentioned previously, bacterial formyl peptides are bound by FPR, inducing chemotaxis of inflammatory cells to sites of bacterial infection. We are currently investigating Listeria monocytogenes infection in mice lacking FPR, with the goal of determining whether this mechanism of inducing inflammation in response to formyl peptides impacts upon CD8 T cell responses.
