Projects and Grants
Control of cross-presentation by signals from TLR
Cross-presentation is the process of presentation of exogenous phagocytosed antigens by major histocompatibility complex (MHC) class I molecules. We focus on antigens acquired by dendritic cells (DC) through phagocytosis, a primary means by which DC internalize and degrade not only microorganisms but also apoptotic cells. We have shown that TLR control phagosome maturation and presentation of antigens by MHC class II molecules. Here we ask: 1) Do TLR control cross-presentation, and if so what is the molecular basis for this control? 2) Is provision of CD4 T cell help to cross-presented antigen regulated by signals from TLR? Our studies here have implications in viral and anti-tumor immunity.
Molecular basis for the superiority of viable vaccines
Vaccination induces a state of immune preparedness by exposing the host to signature components from select pathogens. Although some vaccine preparations can induce protective immunity, there is room for improvement, as certain poorly characterized aspects of natural infection (not incorporated in most vaccines) are particularly effective in inducing the right combination of signals for generating protective immunity. We are working to define the nature of these signals, and delineate the unique receptors and innate immune pathways that they trigger. We hope this knowledge will guide us towards significantly improved vaccine design strategies.
Tumor immunotherapy using ligands for Toll-like and Nod-like receptors
Having been derived from self and lacking microbial structures, tumors are poor at inducing activation of the adaptive immune response. We have shown that the physical presence of phagocytosed antigen and TLR ligands within the same phagosome results in optimal antigen presentation within MHC class II molecules, and successful activation of CD4 T cells. We have thus engineered transplantable tumor cells that express TLR ligands with the prediction that these cells would induce potent CD4 T cell help to tumor-specific CD8 T cells. We have found that TLR ligand bearing tumors fail to develop within syngeneic mice. We are now characterizing the nature of the immune response responsible for rejecting these tumors. Our studies should pave the way to improved tumor immunotherapeutic strategies.
Innate immune recognition of infected and uninfected apoptotic cells
The immunosuppressive nature of apoptotic cell clearance must sometimes coexist with the necessarily inflammatory nature of infection. We have found that pathogens particularly adept at triggering apoptosis preferentially induce T helper 17 (TH17) mediated immunity. We have assigned an important role to phagocytosis of infected apoptotic cells in contributing signals for the development of TH17 cells. We are now investigating the pathways of innate recognition of infected apoptotic cells. Given that infected apoptotic cells comprise signals derived from both self and non-self, we also seek to define the regulatory mechanisms that prevent activation of TH17 cells with specificities to apoptotic cell derived self antigens. Our work should reveal the reasons behind the preferential association of TH17 cells with autoimmunity.
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