title: Dendritic cells promote expansion and survival of aberrant TCR-negative intraepithelial lymphocyte lines from refractory celiac disease type II patients.
abstract: Celiac disease (CD) patients who fail to respond to a gluten-free diet suffer from refractory celiac disease (RCD). A marked expansion of intraepithelial lymphocytes (IEL) lacking surface TCR/CD3 expression characterizes the RCD subtype II. In up to 50% of RCDII patients these so-called aberrant IEL (a-IEL) develop into lymphoma and can disseminate into other tissues. Elevated levels of Interleukin-15 (IL-15) in the intestine of CD and RCD patients likely contribute to the expansion of a-IEL. Here, we investigated if interactions with other cells might also influence a-IEL expansion. Similar to IL-15, cells from the monocyte lineage, particularly mature dendritic cells (DCs), promoted proliferation, prevented apoptosis and induced IFNγ secretion of a-IEL derived from RCDII biopsies (RCDII cell lines), which in turn induced CXCL10. In contrast to IL-15, mature DCs did not induce proliferation of regular TCR(+)IEL lines, generated from CD biopsies and IL-15-blocking antibodies did not inhibit DC-induced proliferation of RCDII cell lines. Furthermore, proliferation was dependent on cell-cell contact, but independent of the HLA-genotype of the stimulating cells. Our results suggest that contact with DC, either in the epithelium or upon dissemination, contributes to uncontrolled expansion of a-IEL in RCDII, independent of HLA-genotype and IL-15.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Frederike
authors.initials: F
authors.lastname: Schmitz
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jennifer M-L
authors.initials: JM
authors.lastname: Tjon
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: van Bergen
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: F.Koning@lumc.nl.
authors.forename: Frits
authors.initials: F
authors.lastname: Koning
mesh_terms: D019138:Antibodies, Blocking / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D002446:Celiac Disease / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D054357:Chemokine CXCL10 / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology*; D019073:HT29 Cells; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D019409:Interleukin-15 / Q000096:biosynthesis / Q000276:immunology; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology; D009000:Monocytes / Q000276:immunology; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D019138:Antibodies, Blocking; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; C569274:IL15 protein, human; D019409:Interleukin-15; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D007371:Interferon-gamma
keywords: Aberrant intraepithelial lymphocytes; CD; Dendritic cells; EATL; IEL; Intraepithelial lymphocytes; RCD; Refractory coeliac disease; T-IEL, TCR+/CD3+ IEL; a-IEL; aberrant IEL; coeliac disease; enteropathy associated T cell lymphoma; intraepithelial lymphocytes; refractory coeliac disease