title: A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease.
abstract: MICA molecules interact with the NKG2D-activating receptor on human NK and CD8 T cells. We investigated the participation of the MICA/NKG2D pathway in the destruction of intestinal epithelium by intraepithelial T lymphocytes (IEL) in Celiac disease and its premalignant complication, refractory sprue. We show that MICA is strongly expressed at epithelial cell surface in patients with active disease and is induced by gliadin or its p31-49 derived peptide upon in vitro challenge, an effect relayed by IL-15. This triggers direct activation and costimulation of IEL through engagement of NKG2D, leading to an innate-like cytotoxicity toward epithelial targets and enhanced TCR-dependent CD8 T cell-mediated adaptive response. Villous atrophy in Celiac disease might thus be ascribed to an IEL-mediated damage to enterocytes involving NKG2D/MICA interaction after gliadin-induced expression of MICA on gut epithelium. This supports a key role for MIC/NKG2D in the activation of intraepithelial immunity in response to danger.
authors.affiliation: Equipe Avenir INSERM, Hôpital Necker-Enfants Malades, 75015 Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Hüe
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Mention
authors.forename: Renato C
authors.initials: RC
authors.lastname: Monteiro
authors.forename: ShaoLing
authors.initials: S
authors.lastname: Zhang
authors.forename: Christophe
authors.initials: C
authors.lastname: Cellier
authors.forename: Jacques
authors.initials: J
authors.lastname: Schmitz
authors.forename: Virginie
authors.initials: V
authors.lastname: Verkarre
authors.forename: Nassima
authors.initials: N
authors.lastname: Fodil
authors.forename: Seiamak
authors.initials: S
authors.lastname: Bahram
authors.forename: Nadine
authors.initials: N
authors.lastname: Cerf-Bensussan
authors.forename: Sophie
authors.initials: S
authors.lastname: Caillat-Zucman
mesh_terms: D001284:Atrophy / Q000276:immunology / Q000473:pathology; D002446:Celiac Disease / Q000097:blood / Q000276:immunology* / Q000473:pathology; D003601:Cytotoxicity Tests, Immunologic; D020895:Enterocytes / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005903:Gliadin / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D019409:Interleukin-15 / Q000276:immunology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D007421:Intestine, Small / Q000276:immunology / Q000473:pathology; D055655:NK Cell Lectin-Like Receptor Subfamily K; D014176:Protein Biosynthesis; D011506:Proteins / Q000187:drug effects / Q000276:immunology*; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D011971:Receptors, Immunologic / Q000276:immunology*; D055607:Receptors, Natural Killer Cell; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: C089801:HCG9 non-protein coding RNA, human; D019409:Interleukin-15; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011506:Proteins; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D005903:Gliadin