Our laboratory is primarily interested in the mechanism of immune regulation by innate immunity in the context of tumors, infections and autoimmune diseases. By understanding how the immune system deals with microbes, tumors and self, we aim to design effective vaccines and therapeutics against cancer and infectious diseases. Presently our study focuses on two classes of proteins: heat shock proteins (HSPs) and Toll-like receptors (TLRs), both of which have been implicated as master regulators of immunity. We and others have discovered that the function of TLRs is dependent on the integrity of the HSP gp96 (or grp94) in the endoplasmic reticulum. Furthermore, depending on its expression level and its subcellular localization, gp96 can initiate systemic autoimmune disease as well as tumor-specific immunity, both of which have a significant clinical relevance. Using a combination of genetic, cell biological, biochemical and immunological tools, we aim to pinpoint the precise mechanism of TLR-gp96 interaction and define the functions of gp96 in hematopoiesis and in the functions of various cellular components in the immune system. In addition, since gp96 is also an important molecule in mediating the unfolded protein response (UPR), works are ongoing to dissect the roles of gp96 in organ development and oncogenesis, and to develop gp96-specific inhibitors for the treatment of diseases with a heavy pathogenic component of inflammation and metabolic dysregulation. Our study has a broad implication in understanding how the immune system operates physiologically and during pathological conditions, in light of the critical roles of TLRs and the UPR in the evolution, function and regulation of the immune response.