Immune responses to pathogens and cancer involve a complex interplay between cells that present antigen and immune cells that mediate effector functions in the defense of the host against these foreign invaders. Analysis of antigen processing, presentation and host defense have mostly involved studying pathways in which proteins are degraded into small peptides which are subsequently presented to the immune system. Recently, a novel pathway for antigen presentation to T cells by the major histocompatibility complex class I-like molecule, CD1, has been revealed. CD1 molecules have been shown to present glycolipids derived from Mycobacteria species, rather than peptides, to T cells. Murine and human CD1d molecules are recognized by a novel subpopulation of T cells called NK T cells. NK T cells produce both Th1 and Th2 cytokines and appear to be important in regulating and/or mediating immune responses to pathogens, such as Toxoplasma and adenovirus. The hypothesis to be tested in this application is that CD1d molecular play a direct (via antigen presentation) and indirect (via regulation of NK T cells) role in antiviral host defense. To address this hypothesis, the following aims are proposed: 1. Analyze the mechanisms by which CD1d molecules associate with their ligands and present these ligands to NK T cells; 2. Identify the ligands bound to CD1d molecules from virus- infected cells; 3. Analyze viral immunopathogenesis in normal and CD1d1-deficient mice; 4. Evaluate the physical and functional association of virus-encoded immune evasion molecules with CD1d. These proposed studies should provide a better understanding of the interactions between CD1 molecules and NK T cells vis-a-vis their role in antiviral immunity. This work will also have wide-ranging applications in the development of new treatments, directed at CD1 and/or NK T cells, not only for infectious diseases, but also for autoimmunity and cancer.
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