Our laboratory is investigating innate and adaptive immune responses to infection by pathogenic organisms. We have established two model systems to characterize innate immunity and antigen specific T cell responses. The first focuses on the intracellular bacterium Listeria monocytogenes. Mice infected with L. monocytogenes develop a rapid inflammatory response that is followed by a robust and highly protective T cell mediated immune response. The early inflammatory response is essential for survival and monocyte recruitment to sites of infection is central to this process. Our laboratory is characterizing the recruitment of monocytes from the bone marrow into the bloodstream and infected tissues following systemic infection with L. monocytogenes. We have found that the CCR2 chemokine receptor is essential for monocyte emigration from the bone marrow and that cellular infection with L. monocytogenes induces the production of MCP-1, the ligand for CCR2. Current studies are investigating the in vivo signaling mechanisms that drive the recruitment of inflammatory cells from bone marrow to infected tissues.
To characterize adaptive immunity, we have determined the antigen specificity of CD8 T cells responding to L. monocytogenes and, using MHC class I tetramers, have measured and characterized the in vivo expansion of distinct T cell populations during the course of active bacterial infection. These studies have shown that CD8 T cells responding to L. monocytogenes infection can be divided into two distinct populations that differ in their MHC restriction, peptide specificity and in vivo response kinetics. The first T cell population to respond to L. monocytogenes infection is restricted by H2-M3 MHC class Ib molecules, which present N-formyl methionine bacterial peptides to CD8 T cells. This T cell response is very rapid and quantitatively substantial, but it does not give rise to a large memory T cell population. The second T cell population is restricted by conventional MHC class Ia molecules. This T cell response is slower than the H2-M3 restricted T cell response but it provides a large populations of memory T cells which protect mice from secondary infection with L. monocytogenes. Our laboratory is currently investigating the cellular and molecular mechanisms that are responsible for the rapid primary response of H2-M3 restricted T cells and the dramatic memory response of MHC class Ia restricted T cells. We believe that these studies will provide fundamental information about T cell responses to bacterial infection and the generation and maintenance of T cell memory.
Our second area of interest concerns the immune response to the fungal pathogen Aspergillus fumigatus. This spore forming mold is an important cause of infection in the immunocompromised host. Our laboratory is characterizing the recruitment of neutrophils and monocytes to the lungs of mice infected with A. fumigatus spores. We have found that Dectin-1, a receptor expressed on alveolar macrophages, plays an important role in the innate immune response to fungal spores. Our studies demonstrate that germinating A. fumigatus spores trigger innate immune responses. Selective responses to germinating spores result from stage-specific display on beta-glucans, a major ligand for Dectin-1, on the spore surface.
We are also characterizing the CD4 T cell response to A. fumigatus infection. Studies in bone marrow transplant models have demonstrated that CD4 T cells can provide protection against invasive A. fumigatus infections. We have generated T cell receptor transgenic mice that are specific for A. fumigatus and are using these mice to characterize in vivo priming, expansion and differentiation of fungus specific CD4 T cells. Current studies are determining the impact of innate immune responses on the subsequent differentiation of A. fumigatus specific CD4 T cells.
