title: DNAM-1 mediates epithelial cell-specific cytotoxicity of aberrant intraepithelial lymphocyte lines from refractory celiac disease type II patients.
abstract: In refractory celiac disease (RCD), intestinal epithelial damage persists despite a gluten-free diet. Characteristic for RCD type II (RCD II) is the presence of aberrant surface TCR-CD3(-) intraepithelial lymphocytes (IELs) that can progressively replace normal IELs and eventually give rise to overt lymphoma. Therefore, RCD II is considered a malignant condition that forms an intermediate stage between celiac disease (CD) and overt lymphoma. We demonstrate in this study that surface TCR-CD3(-) IEL lines isolated from three RCD II patients preferentially lyse epithelial cell lines. FACS analysis revealed that DNAM-1 was strongly expressed on the three RCD cell lines, whereas other activating NK cell receptors were not expressed on all three RCD cell lines. Consistent with this finding, cytotoxicity of the RCD cell lines was mediated mainly by DNAM-1 with only a minor role for other activating NK cell receptors. Furthermore, enterocytes isolated from duodenal biopsies expressed DNAM-1 ligands and were lysed by the RCD cell lines ex vivo. Although DNAM-1 on CD8(+) T cells and NK cells is known to mediate lysis of tumor cells, this study provides, to our knowledge, the first evidence that (pre)malignant cells themselves can acquire the ability to lyse epithelial cells via DNAM-1. This study confirms previous work on epithelial lysis by RCD cell lines and identifies a novel mechanism that potentially contributes to the gluten-independent tissue damage in RCD II and RCD-associated lymphoma.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands. j.m.l.tjon@lumc.nl
authors.forename: Jennifer M-L
authors.initials: JM
authors.lastname: Tjon
authors.forename: Yvonne M C
authors.initials: YM
authors.lastname: Kooy-Winkelaar
authors.forename: Greetje J
authors.initials: GJ
authors.lastname: Tack
authors.forename: A Mieke
authors.initials: AM
authors.lastname: Mommaas
authors.forename: Marco W J
authors.initials: MW
authors.lastname: Schreurs
authors.forename: Marco W
authors.initials: MW
authors.lastname: Schilham
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Mulder
authors.forename: Jeroen
authors.initials: J
authors.lastname: van Bergen
authors.forename: Frits
authors.initials: F
authors.lastname: Koning
mesh_terms: D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D018938:Caco-2 Cells; D002446:Celiac Disease / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D019073:HT29 Cells; D006801:Humans; D039001:Integrin alpha Chains / Q000276:immunology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020014:K562 Cells; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; D039001:Integrin alpha Chains; C091367:alpha E integrins