title: Glucose-regulated protein 94/glycoprotein 96 elicits bystander activation of CD4+ T cell Th1 cytokine production in vivo.
abstract: Glucose-regulated protein 94 (GRP94/gp96), the endoplasmic reticulum heat shock protein 90 paralog, elicits both innate and adaptive immune responses. Regarding the former, GRP94/gp96 stimulates APC cytokine expression and dendritic cell maturation. The adaptive component of GRP94/gp96 function reflects a proposed peptide-binding activity and, consequently, a role for native GRP94/gp96-peptide complexes in cross-presentation. It is by this mechanism that tumor-derived GRP94/gp96 is thought to suppress tumor growth and metastasis. Recent data have demonstrated that GRP94/gp96-elicited innate immune responses can be sufficient to suppress tumor growth and metastasis. However, the immunological processes activated in response to tumor Ag-negative sources of GRP94/gp96 are currently unknown. We have examined the in vivo immunological response to nontumor sources of GRP94/gp96 and report that administration of syngeneic GRP94/gp96- or GRP94/gp96-N-terminal domain-secreting KBALB fibroblasts to BALB/c mice stimulates CD11b(+) and CD11c(+) APC function and promotes bystander activation of CD4(+) T cell Th1 cytokine production. Only modest activation of CD8(+) T cell or NK cell cytolytic function was observed. The GRP94/gp96-dependent induction of CD4(+) T cell cytokine production was markedly inhibited by carrageenan, indicating an essential role for APC in this response. These results identify the bystander activation of CD4(+) T lymphocytes as a previously unappreciated immunological consequence of GRP94/gp96 administration and demonstrate that GRP94/gp96-elicited alterations in the in vivo cytokine environment influence the development of CD4(+) T cell effector functions, independently of its proposed function as a peptide chaperone.
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Julie C
authors.initials: JC
authors.lastname: Baker-LePain
authors.forename: Marcella
authors.initials: M
authors.lastname: Sarzotti
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Nicchitta
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000096:biosynthesis / Q000502:physiology*; D024201:Bystander Effect / Q000276:immunology*; D039481:CD11b Antigen / Q000096:biosynthesis; D039521:CD11c Antigen / Q000096:biosynthesis; D017252:CD3 Complex / Q000096:biosynthesis; D015704:CD4 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis*; D003602:Cytotoxicity, Immunologic; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D018840:HSP70 Heat-Shock Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000502:physiology*; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D008221:Lymphoid Tissue / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010586:Phagocytes / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D039481:CD11b Antigen; D039521:CD11c Antigen; D017252:CD3 Complex; D015704:CD4 Antigens; D016207:Cytokines; D018840:HSP70 Heat-Shock Proteins; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; C018551:glucose-regulated proteins; C052646:sarcoma glycoprotein gp96 rejection antigens; D007371:Interferon-gamma