Although the ability of gp96 to activate APCs and generate CD8 CTLs against peptides they chaperone through interaction with the endocytic receptors CD91 is supported by solid evidence, its biological relevance in immune surveillance is debated. We have used an evolutionary approach to determine whether gp96 interacts with receptors expressed on APCs and promotes MHC class I cross-presentation of minor histocompatibility Ags (H-Ags) to CTLs in the frog Xenopus. We show that in Xenopus gp96 binds the CD91 homolog at the surface of peritoneal leukocytes, and that this binding is inhibited by molar excess of unlabeled gp96 or the CD91 ligand alpha2-macroglobulin, by anti-CD91 Ab and by the specific CD91 antagonist receptor-associated protein. Surface binding followed by internalization of gp96 was confirmed by fluorescent microscopy. Furthermore, adoptive transfer of peritoneal leukocytes pulsed with as little as 800 ng of gp96 chaperoning minor H-Ags, but not minor H-Ag-free gp96, induces potent CD8 T cell infiltration and Ag-specific accelerated rejection of minor H-locus disparate skin grafts. Inhibition of gp96-CD91 interaction by pretreatment with anti-CD91 Ab and receptor-associated protein impairs both CD8 T cell infiltration and acute skin graft rejection. These data provide evidence of the conserved ability of gp96 to facilitate cross-presentation of chaperoned Ags by interacting with CD91. The persistence of this biological process for >350 million years that separate mammals and amphibians from a common ancestor strongly supports the proposition that gp96 and CD91 are critically involved in immune surveillance.
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http://dx.doi.org/10.4049/jimmunol.180.5.3176 | DOI Listing |
J Clin Med
December 2024
Department of General Pathology and Pathologic Anatomy, Faculty of Medicine, University of Rijeka, Braće Branchetta 20, 51000 Rijeka, Croatia.
: In this paper, we investigate the association of glycoprotein 96 (GP96) and androgen receptor (AR) expression with clinicopathological factors, additional axillary lymph node burden, and their potential role in predicting 5-year overall survival (OS) and disease-free survival (DFS) in breast cancer (BC) patients with sentinel lymph node (SLN) involvement. We also explore the prognostic value of the presence of extranodal extension (ENE) in SLN. : We retrospectively enrolled 107 female patients with cT1-T2 invasive BC and positive SLN biopsy.
View Article and Find Full Text PDFCell Stress Chaperones
December 2024
Service d'Immunologie, Faculté de Médecine, de Pharmacie et d'Odontostomatologie, Université Cheikh Anta DIOP, Avenue Cheikh Anta DIOP, BP: 5005, Dakar, Senegal.
Malaria caused by Plasmodium spp., is a major public health issue in sub-Saharan Africa. The fight against malaria has stalled due to increasing resistance to treatments and insecticides.
View Article and Find Full Text PDFJ Hazard Mater
December 2024
Institute of Translational Pharmacology (IFT), National Research Council (CNR), Via Ugo La Malfa 153, Palermo 90146, Italy. Electronic address:
The innate immune system is the first player involved in the recognition/interaction with nanomaterials. Still, it is not the only system involved. The co-evolution of the microbiota with the innate immune system built an interdependence regulating immune homeostasis that is poorly studied.
View Article and Find Full Text PDFJ Exp Med
March 2025
Department of Immunobiology, University of Lausanne, Epalinges, Switzerland.
Toll-like receptors (TLRs) are central to initiate immune responses against invading pathogens. To ensure host defense while avoiding aberrant activation leading to pathogenic inflammation and autoimmune diseases, TLRs are tightly controlled by multilevel regulatory mechanisms. Through a loss-of-function genetic screen in a reporter cell line engineered to undergo cell death upon TLR7-induced IRF5 activation, we identified here CCDC134 as an essential factor for TLR responses.
View Article and Find Full Text PDFVaccines (Basel)
August 2024
Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Immune cells undergo metabolic reprogramming to meet the demands associated with immune responses. The effects of aging on these pathways and on the metabolic phenotype of the immune cells participating in antibody responses to vaccines are still largely unknown. Here we used a vaccine for SARS-CoV-2 that utilizes the cellular heat shock chaperone glycoprotein 96 (gp96), engineered to co-express SARS-CoV-2 Spike (spike) protein (gp96-Ig-S).
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