The research of my laboratory is focused on two of the MHC class Ib molecules: H2-M3 and CD1. These molecules have unusual binding specificity for antigens which are conserved in bacteria. H2-M3 presents N -formylated bacterial peptides to CD8 + cytotoxic T cells while CD1 presents microbial lipid and glycolipid antigens to several distinct subsets of T cells. Over the past few years, my laboratory has developed several animal models to study the role of M3 and CD1 in T cell development and the function of these class Ib-restricted T cells in the control of autoimmunity and infectious diseases.
Project 1. Role of M3 in T Cell Development and Bacterial Infection H2-M3 has unique specificity for N-formylated peptides and can present peptides derived from mitochondria and intracellular bacteria, which initiate protein synthesis with formyl-methionine. My lab is interested in understanding how and where M3 interacts with its antigens, and how M3 specific T cells are developed. Toward this end, we have developed several monoclonal antibodies against M3 molecules, which allows us to study the M3 expression under normal and pathological conditions and examine the intra-cellular trafficking of M3. To understand how M3-specific T cells are developed, we have generated transgenic mice that express T cell receptors specific for a complex of M3 and a bacteria antigen from Listeria monocytogene. The transgenic mice will be used to study the requirements for the thymic selection and memory development of the uniquely restricted T cell lineage. In addition, we have generated M3-deficient and MHC class Ia/M3-deficient mice to determine the relative contribution of class1a and class Ib-restricted response against bacterial infection.
Project 2. The Regulation and Function of Murine CD1d (group2 CD1) molecules Unlike MHC class I and class II molecules which present peptide antigens to T cells, CD1 molecules present lipid and glycolipid antigens to T cells. We have generated CD1d-deficient mice and found that CD1d is essential for the development of a unique subset of immunoregulatory T cells, the NKT cells. Lack of NKT cells in CD1d-deficient NOD mice leads to exacerbation and early onset of autoimmune diabetes, suggesting an important regulatory role of CD1d-restricted NKT cells. To examine the effect of CD1d surface density and expression pattern on the development of NKT cells, we have generated several CD1d transgenic mouse models. We found that the distinct expression pattern of CD1d1 on the hematopoietic cells establishes a narrow window between positive and negative selection of NKT cells. Interestingly, one of our CD1d transgenic models spontaneously develop liver pathology characterized by increases in liver mass and resident leukocyte cell numbers. Currently, we are using both genetic and molecular approaches to understand how changes to the CD1d expression program affect NKT cell function and to determine the role of NKT cells in liver pathogenesis. Because the cell surface density of CD1d has both quantitative and qualitative effect on NKT cell repertoire, we are in the process to identify cis-regulatory elements and transcription factors that are involved in the cell type-specific expression of CD1d.
Project 3. Role of Group1 CD1 in Infection and Autoimmunity While group2 CD1-restricted NKT cells have been attributed to play an immunoregulatory role, group 1 CD1 has been shown to be involved in specific recognition of a highly conserved class of microbial antigens by T cells. We have generated transgenic mice that express human CD1a, CD1b, and CD1c to study the role of group 1 CD1-restricted responses in the defense against various microbial pathogens and to test the viability of lipid vaccines to confer resistance to infectious agents, such as Mycobacterium tuberculosis. Non-microbial glycolipids, such as self-glycolipids GM1, GM2 and sulfatide have been shown to bind group 1 CD1. We will also use the hCD1 transgenic mouse as an animal model to examine the possible role of self-glycolipids and group 1 CD1 in autoimmunity.