Zihai Li, M.D., Ph.D.
Associate Professor

University of Connecticut Health Center
Department of Immunology
263 Farmington Avenue
Farmington, CT 06030-1601
Telephone: (860) 679-7979
Fax: (860) 679-1265
email: Zli@up.uchc.edu

 Dr. Zihai Li  

Our laboratory is primarily interested in the mechanism of immune regulation by the 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 recently that the function of TLRs is dependent on the integrity of a HSP gp96 (or grp94) in the endoplasmic reticulum (Harding C.V. gp96 leads the way for Toll-like receptors. Immunity. 2007 26:141-3). Furthermore, depending on the level and location, changes of gp96 expression can initiate systemic autoimmune diseases as well as tumor-specific immunity, 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 the implications of such in hematopoiesis and in the functions of various cellular components in the immune system. Our study has a broad implication in understanding how the immune system operates in light of the critical roles of TLR in the evolution, function and regulation of the immune system.
         
We take pride in sharing our expertise with trainees at all levels including graduate students, medical residents, clinical fellows as well as postdoctoral fellows. At the same time, trainees are expected to be challenged experimentally and intellectually in the laboratory. They are encouraged to choose projects under the general conceptual frame as outlined above and are expected to function independently.

We are seeking highly motivated postdoctoral fellows to lead a recent NIH-awarded project. Ideal candidates should have a Ph.D. in immunology and have a strong background in cellular immunology and biochemistry. Send your CV and names of three references to Dr. Li (zli@up.uchc.edu).
confocal images
We have demonstrated recently that HSP gp96 is a master chaperone for TLRs and macrophage-specific gp96 null mice are highly susceptible to Listeria infection. Shown are confocal images of spleen sections from uninfected wild type mice (left), Listeria-infected wild type mice (middle) and macrophage-specific gp96 null mice (right) (red: Listeria, green: Gr1+ granulocytes, blue: B220+ B cells) (Images from Yi Yang in the laboratory)

Selected Publications:

Yang Y, Liu B, Dai J, Srivastava PK, Zammit DJ, Lefrancois L, Li Z (2007) Heat shock protein gp96 is a master chaperone for Toll-like receptors and is important in the innate function of macrophages.
Immunity 26(2):215-26.

Dai J, Liu B, Ngoi SM, Sun S, Vella AT, Li Z (2007) TLR4 Hyperresponsiveness via cell surface expression of heat shock protein gp96 potentiates suppressive function of regulatory T cells. J Immunol 178(5):3219-25.

Dai J, Liu B, Cua DJ, Li Z (2007) Essential roles of IL-12 and dendritic cells but not IL-23 and macrophages in lupus-like diseases initiated by cell surface HSP gp96. Eur J Immunol 37(3):706-715.

Liu B, Yang Y, Dai J, Medzhitov R, Freudenberg MA, Zhang PL, Li Z. (2006) TLR4 up-regulation at protein or gene level is pathogenic for lupus-like autoimmune disease. J Immunol 177(10):6880-8.

Li Z, Qiao Y, Liu B, Laska EJ, et al. (2005) Combination of imatinib mesylate with autologous leukocyte-derived heat shock protein 70 and chronic myelogenous leukemia. Clin Cancer Res 11(12):4460-8.

Yang Y, Li Z (2005) Roles of heat shock protein gp96 in the ER quality control: redundant or unique function? Mol Cells 20(2):173-82.

Zheng H and Li Z (2004) Cutting Edge: Cross-presentation of cell-associated antigens to MHC class I molecule is regulated by a major transcription factor for molecular chaperones. J Immunol 173(10):5929-33.

DeFillipo AM, Dai J, Li Z (2004) Heat shock-induced dendritic cell maturation is coupled by transient aggregation of ubiquitinated proteins independently of heat shock factor 1 or inducible heat shock protein 70. Mol Immunol 41(8):785-92.

Millar DG, Garza KM, Odermatt B, Elford AR, Li Z and Ohashi PS (2003) Hsp70 promotes antigen presenting cell function and converts T cell tolerance to autoimmunity in vivo. Nat Med 9(12):1469 –1476.

Liu B, Dai J, Zheng H, Stoilova D, Sun S and Li Z (2003) Cell surface expression of an endoplasmic reticulum resident heat shock protein gp96 triggers MyD88-dependent systemic autoimmune diseases. Proc Natl Acad Sci USA 100:15824-15829.

Zheng H, Benjamin IJ, Basu S and Li Z (2003) Heat shock factor 1 - independent activation of dendritic cells by heat shock: implication for the uncoupling of heat-mediated immunoregulation from heat shock response. Eur J Immunol 33:1754-1762.

Dai J, Liu B, Caudill MM, Zheng H, Qiao Y, Podack E AND Li Z (2003) Cell surface expression of heat shock protein gp96 enhances cross-presentation of cellular antigens and the generation of tumor-specific T cell memory. Cancer Immun 3:1-11.

Liu B, DeFilippo A and Li Z (2002) Overcoming immune tolerance to cancer by heat shock protein vaccines. Mol Cancer Ther 1: 1147-1151.

Li Z, Dai J, Zheng H, Liu B and Caudill M (2002) An integrated view of the roles and mechanisms of heat shock protein gp96-peptide complex in eliciting immune response. Front Biosci 7:731-751.

Li Z, Menoret A and Srivastava PK (2002) Roles of heat shock proteins in antigen presentation and cross-presentation. Curr Opin Immunol 14:45-51.

Zheng H, Dai J, Stoilova D and Li Z (2001) Surface targeting of an intracellular heat shock protein gp96 induces dendritic cell maturation and anti-tumor immunity. J Immunol 167:6731-6735.

Caudill M and Li Z (2001) HSPPC-96: a personalized cancer vaccine. Exp Opin Bio Ther 1(3):539-548.