A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease.
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.
Hüe
Sophie
S
Equipe Avenir INSERM, Hôpital Necker-Enfants Malades, 75015 Paris, France.
Mention
Jean-Jacques
JJ
Monteiro
Renato C
RC
Zhang
ShaoLing
S
Cellier
Christophe
C
Schmitz
Jacques
J
Verkarre
Virginie
V
Fodil
Nassima
N
Bahram
Seiamak
S
Cerf-Bensussan
Nadine
N
Caillat-Zucman
Sophie
S
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
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