| CD1 molecules, similar in structure to MHC class I, present lipid antigens to T cells. T cells restricted to the group 1 CD1 molecules CD1a, CD1b and CD1c have been shown to recognize mycobacterial lipid antigens and are found at greater frequencies in humans infected with Mycobacterium tuberculosis (Mtb). Group 1 CD1-restricted T cells may therefore contribute to protective immunity against Mycobacteria. However, as mice lack the group 1 CD1 genes, the role group 1 CD1-restricted T cells play in infection remains unknown. To address the need for a small animal model of group 1 CD1-restricted immunity, our lab has generated human group 1 CD1 transgenic mice (hCD1Tg) that express the human group 1 CD1 molecules and develop group 1 CD1-restricted T cells.;We have utilized hCD1Tg mice to investigate the in vivo phenotype, dynamics and function of group 1 CD1-restricted T cells. We found that group 1 CD1-restricted T cells are present in CD8+, CD4 + and DN T cell subsets and have diverse TCR usage. In addition, group 1 CD1-restricted T cells in hCD1Tg mice recognize some of the same mycobacterial antigens described in humans. Immunization of hCD1Tg mice with Mtb lipids elicits group 1 CD1-restricted T cell secretion of IFN-gamma. In contrast to group 2 CD1-restricted NKT cells, which rapidly respond to initial stimulation but exhibit anergy upon re-exposure, group 1 CD1-restricted T cells have delayed primary responses and more rapid secondary responses, similar to conventional T cells. Furthermore, the numbers of group 1 CD1-expressing antigen presenting cells in hCD1Tg mice are altered over the course of mycobacterial infection. Taken together, our data show that group 1 CD1-restricted T cells participate in adaptive immunity against Mtb. Although Mtb remains responsible for significant mortality worldwide, the available vaccine is not consistently protective, demonstrating the need for improved Mtb vaccines that stimulate potent cellular responses. As the group 1 CD1 molecules display little polymorphism and the lipid antigens they present are more widely conserved among bacterial species than are protein antigens, lipids that stimulate group 1 CD1-restricted T cells are attractive targets for new Mtb subunit vaccine development. |
