Dendritic cells (DCs) play critical roles in tolerance as well as in immunity. Detailed understanding of factor(s) and condition(s) leading to such divergent states of DCs is critical in understanding immune responses against pathogens and tumors, as well as self antigens DCs express pattern recognition receptors such as Toll-like receptors (TLRs) on the cell surface. At least 10 TLRs with distinct ligand binding specificities have been identified. Although TLRs are evolved to sense microbial products, the existence of endogenous TLR activators has been proposed. Recent studies suggest that TLR2 and TLR4 are also the receptors for a ubiquitous mammalian heat shock protein gp96 of the endoplasmic reticulum. The presence of cell surface receptor for an intracellular molecule suggests that the export of gp96 from cells must be regulated in vivo and uncontrolled gp96 export must have immunological consequences. This proposal aims to address the immunological significance of cell surface gp96 in immunity on an organismal level, by using novel transgenic mouse models where gp96 is targeted to cell surfaces broadly. We demonstrated that surface translocation of gp96 in vivo triggers a MyD88-dependent systemic autoimmunity, which provides perhaps the strongest evidence yet for gp96 as an endogenous proinflammatory molecule. Two broad hypotheses will be addressed. First, chronic stimulation of DCs bygp96 breaks peripheral T cell tolerance and induces autoimmune diseases. Second, gp96 export is critically important for the regulation of T cell immunity. This line of work should contribute to the increasing appreciation that the immune system evolves and functions not only against exogenous pathogen-associated molecular patterns, but also towards endogenous """"""""danger molecules"""""""" of the host. Our proposal therefore should have implications in cancer immunity as well as in autoimmune diseases. Specifically, we aim to: (1) determine if disruption of gp96 retention mechanisms induces DC activation and exacerbates autoimmunity;(2) study the impact of cell surface gp96 on T cell activation and memory; and (3) elucidate the roles of cell surface gp96, in peripheral tolerance, against self-reactive T cells otherwise destined to anergy/tolerance.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100191-04
Application #
7198151
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Howcroft, Thomas K
Project Start
2004-04-07
Project End
2008-09-30
Budget Start
2007-04-01
Budget End
2008-09-30
Support Year
4
Fiscal Year
2007
Total Cost
$225,478
Indirect Cost
Name
University of Connecticut
Department
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Morales, Crystal; Wu, Shuang; Yang, Yi et al. (2009) Drosophila glycoprotein 93 Is an ortholog of mammalian heat shock protein gp96 (grp94, HSP90b1, HSPC4) and retains disulfide bond-independent chaperone function for TLRs and integrins. J Immunol 183:5121-8
Dai, Jie; Liu, Bei; Li, Zihai (2009) Regulatory T cells and Toll-like receptors: what is the missing link? Int Immunopharmacol 9:528-33
Liu, Bei; Li, Zihai (2008) Endoplasmic reticulum HSP90b1 (gp96, grp94) optimizes B-cell function via chaperoning integrin and TLR but not immunoglobulin. Blood 112:1223-30
Dhodapkar, Madhav V; Dhodapkar, Kavita M; Li, Zihai (2008) Role of chaperones and FcgammaR in immunogenic death. Curr Opin Immunol 20:512-7
Han, Jung Min; Park, Sang Gyu; Liu, Bei et al. (2007) Aminoacyl-tRNA synthetase-interacting multifunctional protein 1/p43 controls endoplasmic reticulum retention of heat shock protein gp96: its pathological implications in lupus-like autoimmune diseases. Am J Pathol 170:2042-54
Dai, Jie; Liu, Bei; Ngoi, Soo Mun et al. (2007) TLR4 hyperresponsiveness via cell surface expression of heat shock protein gp96 potentiates suppressive function of regulatory T cells. J Immunol 178:3219-25
Dai, Jie; Liu, Bei; Cua, Daniel J et al. (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 37:706-15
Yang, Yi; Liu, Bei; Dai, Jie et al. (2007) Heat shock protein gp96 is a master chaperone for toll-like receptors and is important in the innate function of macrophages. Immunity 26:215-26
Liu, Bei; Yang, Yi; Dai, Jie et al. (2006) TLR4 up-regulation at protein or gene level is pathogenic for lupus-like autoimmune disease. J Immunol 177:6880-8
Zheng, Hong; Li, Zihai (2004) Cutting edge: cross-presentation of cell-associated antigens to MHC class I molecule is regulated by a major transcription factor for heat shock proteins. J Immunol 173:5929-33

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