gp96 is an immune chaperone in the lumen of the endoplasmic reticulum, for the folding and assembly of multiple key receptors in immune responses including TLRs and integrins. Dysregulation of gp96 has been linked with a number of rheumatoid diseases such as lupus. We discovered very recently that gp96 is also critically required for the stability and in vivo suppressive function of regulatory T cells (Zhang et al., J Clin Invest 2015). Furthermore, we unveiled that gp96 serves as an essential chaperone for folding the cell surface docking receptor for TGFb, GARP (known also as LRRC32), whose expression is thought to be restricted to Tregs and platelets. Intriguingly, we found that B cells but not myeloid cells express GARP upon TLR ligation, and there is a unique population of GARP+ B cells in the steady state in both mouse lupus models and human patients with SLE. In essence, we have now established that gp96 regulates several key aspects of immunity and tolerance. It is required for optimal dendritic cell activation via chaperoning TLRs to initiate immune responses. gp96 also plays essential roles for immune tolerance by endowing suppressive function of Treg cells. The immunity vs. tolerance fate determination thus could be orchestrated by gp96 in a contextual and cell type specific fashion. We hypothesize that gp96 controls immune tolerance by regulating the bioavailability of cell surface TGFb for Tregs and B cells. This is accomplished by the intrinsic chaperone function of gp96 in folding both GARP and integrins, the former is involved in snatching and binding latent TGFb from the extracellular milieu in a paracrine fashion, whereas the latter is involved in TGFb activation. This novel hypothesis will be addressed by the following two specific aims:
Our first Aim will focus on understanding the mechanisms of gp96 in controlling Treg cell function.
Our second Aim will determine the roles of B cell-intrinsic GARP in fundamental B cell biology and the pathogenesis of lupus, by taking advantage of our exciting preliminary data demonstrating the roles of GARP in attenuating experimental lupus. Thus, the two aims will be pursued in both normal and pathogenic conditions. A number of novel genetic models including inducible and cell-specific GARP knockout mice, will be used. We believe that full elucidation of our hypothesis will have fundamental implications in understanding the elusive roles of cell surface TGFb in immune tolerance, as well as in the pathogenesis of lupus.

Public Health Relevance

The immune system is a powerful system for fighting against infections and cancers, but it must be kept in check to avoid autoimmune diseases such as lupus. My laboratory has discovered a key regulator of immunity- versus-tolerance decision: a stress protein called gp96. We will study, for the first time, the actions and mechanisms of gp96 and its important clientele in balancing regulatory T cells and B cells to prevent autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI077283-11A1
Application #
9310818
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Johnson, David R
Project Start
2009-03-01
Project End
2022-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
11
Fiscal Year
2017
Total Cost
$373,750
Indirect Cost
$123,750
Name
Medical University of South Carolina
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29403
Metelli, Alessandra; Salem, Mohammad; Wallace, Caroline H et al. (2018) Immunoregulatory functions and the therapeutic implications of GARP-TGF-? in inflammation and cancer. J Hematol Oncol 11:24
Lin, Ching Ying; Kwon, Hyunwoo; Rangel Rivera, Guillermo O et al. (2018) Sex Differences in Using Systemic Inflammatory Markers to Prognosticate Patients with Head and Neck Squamous Cell Carcinoma. Cancer Epidemiol Biomarkers Prev 27:1176-1185
Thaxton, Jessica E; Wallace, Caroline; Riesenberg, Brian et al. (2017) Modulation of Endoplasmic Reticulum Stress Controls CD4+ T-cell Activation and Antitumor Function. Cancer Immunol Res 5:666-675
Hong, Feng; Mohammad Rachidi, Saleh; Lundgren, Debbie et al. (2017) Mapping the Interactome of a Major Mammalian Endoplasmic Reticulum Heat Shock Protein 90. PLoS One 12:e0169260
Neitzke, Daniel J; Bowers, Jacob S; Andrijauskaite, Kristina et al. (2017) Murine Th17 cells utilize IL-2 receptor gamma chain cytokines but are resistant to cytokine withdrawal-induced apoptosis. Cancer Immunol Immunother 66:737-751
Rachidi, Saleh; Metelli, Alessandra; Riesenberg, Brian et al. (2017) Platelets subvert T cell immunity against cancer via GARP-TGF? axis. Sci Immunol 2:
Rachidi, Saleh; Wallace, Kristin; Wrangle, John M et al. (2016) Neutrophil-to-lymphocyte ratio and overall survival in all sites of head and neck squamous cell carcinoma. Head Neck 38 Suppl 1:E1068-74
Anas, Adam A; de Vos, Alex F; Hoogendijk, Arie J et al. (2016) Endoplasmic reticulum chaperone gp96 in macrophages is essential for protective immunity during Gram-negative pneumonia. J Pathol 238:74-84
Zhou, Zejun; Ding, Miao; Huang, Lei et al. (2016) Toll-like receptor-mediated immune responses in intestinal macrophages; implications for mucosal immunity and autoimmune diseases. Clin Immunol 173:81-86
Zhang, Yongliang; Wu, Bill X; Metelli, Alessandra et al. (2015) GP96 is a GARP chaperone and controls regulatory T cell functions. J Clin Invest 125:859-69

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