Areas of Interest
Dr. Li’s 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.
Lab Rotation Projects
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.
Post Docs
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).
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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, Lefrançois 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.
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 (*co-first authors).
Caudill M and Li Z (2001) HSPPC-96: a personalized cancer
vaccine. Exp Opin Bio Ther 1(3):539-548.
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