title: Alternative Splice Transcripts for MHC Class I-like MICA Encode Novel NKG2D Ligands with Agonist or Antagonist Functions.
abstract: MHC class I chain-related proteins A and B (MICA and MICB) and UL16-binding proteins are ligands of the activating NKG2D receptor involved in cancer and immune surveillance of infection. Structurally, MICA/B proteins contain an α3 domain, whereas UL16-binding proteins do not. We identified novel alternative splice transcripts for MICA encoding five novel MICA isoforms: MICA-A, -B1, -B2, -C, and -D. Alternative splicing associates with MICA*015 and *017 and results from a point deletion (G) in the 5' splice donor site of MICA intron 4 leading to exon 3 and exon 4 skipping and/or deletions. These changes delete the α3 domain in all isoforms, and the α2 domain in the majority of isoforms (A, B1, C, and D). Endothelial and hematopoietic cells contained endogenous alternative splice transcripts and isoforms. MICA-B1, -B2, and -D bound NKG2D by surface plasmon resonance and were expressed at the cell surface. Functionally, MICA-B2 contains two extracellular domains (α1 and α2) and is a novel potent agonist ligand for NKG2D. We found that MICA-D is a new truncated form of MICA with weak affinity for NKG2D despite lacking α2 and α3 domains. MICA-D may functionally impair NKG2D activation by competing with full-length MICA or MICA-B2 for NKG2D engagement. Our study established NKG2D binding for recombinant MICA-B1 but found no function for this isoform. New truncated MICA isoforms exhibit a range of functions that may drive unexpected immune mechanisms and provide new tools for immunotherapy.
authors.affiliation: INSERM, UMR1064, LabEx Transplantex, LabEx Immunology-Graft-Oncology, and Hospital/University Institute European Center for Transplantation and Immunotherapy Sciences, Nantes, F44000 France; Centre Hospitalo-Universitaire Nantes, Institut de Transplantation et de Recherche en Transplantation-Urologie-Néphrologie, Institut de Transplantation et de Recherche en Transplantation-Urologie-Néphrologie, Nantes, F44000 France; L'Université Nantes Angers Le Mans, Université de Nantes, Faculté de Médecine, Nantes, F44000 France;
authors.forename: Pierre-Jean
authors.identifier: 0000-0001-5736-5711
authors.initials: PJ
authors.lastname: Gavlovsky
authors.affiliation: INSERM, UMR1064, LabEx Transplantex, LabEx Immunology-Graft-Oncology, and Hospital/University Institute European Center for Transplantation and Immunotherapy Sciences, Nantes, F44000 France; Centre Hospitalo-Universitaire Nantes, Institut de Transplantation et de Recherche en Transplantation-Urologie-Néphrologie, Institut de Transplantation et de Recherche en Transplantation-Urologie-Néphrologie, Nantes, F44000 France; L'Université Nantes Angers Le Mans, Université de Nantes, Faculté de Médecine, Nantes, F44000 France;
authors.forename: Pierre
authors.initials: P
authors.lastname: Tonnerre
authors.affiliation: INSERM, UMR1064, LabEx Transplantex, LabEx Immunology-Graft-Oncology, and Hospital/University Institute European Center for Transplantation and Immunotherapy Sciences, Nantes, F44000 France; Centre Hospitalo-Universitaire Nantes, Institut de Transplantation et de Recherche en Transplantation-Urologie-Néphrologie, Institut de Transplantation et de Recherche en Transplantation-Urologie-Néphrologie, Nantes, F44000 France; L'Université Nantes Angers Le Mans, Université de Nantes, Faculté de Médecine, Nantes, F44000 France;
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gérard
authors.affiliation: L'Université Nantes Angers Le Mans, Université de Nantes, Faculté de Médecine, Nantes, F44000 France; Plateforme MicroPICell Structure Fédérative de Recherche Santé-Institut de Recherche Thérapeutique, Nantes F44000, France; and.
authors.forename: Steven
authors.initials: S
authors.lastname: Nedellec
authors.affiliation: Department of Chemistry and Biochemistry, Seattle Pacific University, Seattle, WA 98119.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Daman
authors.affiliation: Department of Chemistry and Biochemistry, Seattle Pacific University, Seattle, WA 98119.
authors.forename: Benjamin J
authors.identifier: 0000-0001-9785-6670
authors.initials: BJ
authors.lastname: McFarland
authors.affiliation: INSERM, UMR1064, LabEx Transplantex, LabEx Immunology-Graft-Oncology, and Hospital/University Institute European Center for Transplantation and Immunotherapy Sciences, Nantes, F44000 France; Centre Hospitalo-Universitaire Nantes, Institut de Transplantation et de Recherche en Transplantation-Urologie-Néphrologie, Institut de Transplantation et de Recherche en Transplantation-Urologie-Néphrologie, Nantes, F44000 France; L'Université Nantes Angers Le Mans, Université de Nantes, Faculté de Médecine, Nantes, F44000 France; Beatrice.Charreau@univ-nantes.fr.
authors.forename: Béatrice
authors.identifier: 0000-0001-5870-4615
authors.initials: B
authors.lastname: Charreau
mesh_terms: D017398:Alternative Splicing; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005805:Genes, MHC Class I; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms; D020349:Surface Plasmon Resonance
chemical_list: D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; D008024:Ligands; C099187:MHC class I-related chain A; D055655:NK Cell Lectin-Like Receptor Subfamily K; D020033:Protein Isoforms