Dr. Zihai Li’s laboratory is primarily interested in the mechanism of immune regulation by the innate immune system in the context of cancer, infection and autoimmune disease. His research team has made seminal contributions to understanding the immunological properties of heat shock proteins (HSPs) in cancer immunotherapy and immune tolerance. They provided the first genetic evidence linking the heat shock response to antigen cross-presentation and adaptive immunity; pioneered the use of autologous tumor-derived HSP70-peptide complex for the immunotherapy of human leukemia; and discovered that HSP gp96 (known also as grp94 and HSP90b1) in the endoplasmic reticulum is the master molecular chaperone for Toll-like receptors (TLRs). Furthermore, through transgenic mouse models, they have illuminated the importance of the subcellular localization of gp96 in regulating T cell tolerance and systemic lupus erythematosus. Using a combination of genetic, cell biological, biochemical and immunological tools, the Li laboratory presently aims to pinpoint the precise mechanism of gp96-TLR interaction and to understand the implications of such in hematopoiesis and cancer, as well as in the functions of various cellular components of the immune system. This work has broad implications in understanding how the immune system operates physiologically and how it might be harnessed for the prevention and treatment of human diseases in light of the critical role of TLRs in the evolution, function and regulation of the immune system.