title: The stress protein gp96 is not an activator of resting rat bone marrow-derived dendritic cells, but is a costimulator and activator of CD3+ T cells.
abstract: Although low doses of tumor-derived stress protein gp96 elicit protective immunity to the tumor from which it is isolated, protection is lost at high doses because of the induction of immunoregulatory CD4+ T cells. This study evaluated the influence of gp96 on resting rat bone marrow-derived dendritic cells (BMDCs) and purified CD3+ T cells. In contrast to previous reports, gp96 had no effect on adhesion and costimulatory molecule expression by BMDCs, nor did it influence interleukin (IL)-10 and IL-12 secretion or their allostimulatory capacity. Gp96 did not bind to BMDCs but dose-dependently bound to CD4+ and CD8+ T cells. At low concentrations (1 and 25 microg/mL), gp96 acted as a costimulator of CD3+ T cells, inducing proliferation and the secretion of interferon (IFN)-gamma- and IL-10. Gp96 also increased the proliferation of CD28-costimulated CD3+ T cells and their secretion of IFN-gamma, IL-4, and IL-10. Gp96 had no effect at higher concentrations (50 and 100 microg/mL), despite the occurrence of cell surface binding at these concentrations. These findings indicate that gp96 can act as a costimulatory molecule for CD3+ T cells, and an observed increase in the IL-10: IFN-gamma secretion ratio induced by gp96 suggests that it might, at appropriate concentrations, promote a regulatory T-helper 2 (Th2)-like phenotype.
authors.affiliation: Immunobiology Research Unit, School of Medicine and Biomedical Sciences (University of Sheffield), L Floor, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK.
authors.forename: Shabana
authors.initials: S
authors.lastname: Mirza
authors.forename: Munitta
authors.initials: M
authors.lastname: Muthana
authors.forename: Barbara
authors.initials: B
authors.lastname: Fairburn
authors.forename: Laura K
authors.initials: LK
authors.lastname: Slack
authors.forename: Kay
authors.initials: K
authors.lastname: Hopkinson
authors.forename: A Graham
authors.initials: AG
authors.lastname: Pockley
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000502:physiology*; D018106:CD28 Antigens; D017252:CD3 Complex / Q000378:metabolism*; D003713:Dendritic Cells / Q000502:physiology*; D016650:Fluorescein-5-isothiocyanate / Q000494:pharmacology; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000302:isolation & purification / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; D008562:Membrane Glycoproteins; C053387:endoplasmin; D016650:Fluorescein-5-isothiocyanate