title: Defective synthesis or association of T-cell receptor chains underlies loss of surface T-cell receptor-CD3 expression in enteropathy-associated T-cell lymphoma.
abstract: Enteropathy-associated T-cell lymphoma, an often fatal complication of celiac disease, can result from expansion of aberrant intraepithelial lymphocytes in refractory celiac disease type II (RCD II). Aberrant intraepithelial lymphocytes and lymphoma cells are intracellularly CD3epsilon(+) but lack expression of the T-cell receptor (TCR)-CD3 complex on the cell surface. It is unknown what causes the loss of TCR-CD3 expression. We report the isolation of a cell line from an RCD II patient with the characteristic phenotype of enteropathy-associated T-cell lymphoma. We demonstrate that in this cell line the TCR-alpha and -beta chains as well as the CD3gamma, CD3delta, CD3epsilon, and zeta-chains are present intracellularly and that assembly of the CD3gammaepsilon, CD3deltaepsilon, and zetazeta-dimers is normal. However, dimerization of the TCR chains and proper assembly of the TCR-CD3 complex are defective. On introduction of exogenous TCR-beta chains, but not of TCR-alpha chains, assembly and functional cell surface expression of the TCR-CD3 complex were restored. Defective synthesis of both TCR chains was found to underlie loss of TCR expression in similar cell lines isolated from 2 additional patients. (Pre)malignant transformation in RCD II thus correlates with defective synthesis or defective association of the TCR chains, resulting in loss of surface TCR-CD3 expression.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, USA. j.m.l.tjon@lumc.nl
authors.forename: Jennifer M L
authors.initials: JM
authors.lastname: Tjon
authors.forename: Wieke H M
authors.initials: WH
authors.lastname: Verbeek
authors.forename: Yvonne M C
authors.initials: YM
authors.lastname: Kooy-Winkelaar
authors.forename: Binh H
authors.initials: BH
authors.lastname: Nguyen
authors.forename: Arno R
authors.initials: AR
authors.lastname: van der Slik
authors.forename: Allan
authors.initials: A
authors.lastname: Thompson
authors.forename: Mirjam H M
authors.initials: MH
authors.lastname: Heemskerk
authors.forename: Marco W J
authors.initials: MW
authors.lastname: Schreurs
authors.forename: Liesbeth H A
authors.initials: LH
authors.lastname: Dekking
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: D001706:Biopsy; D017252:CD3 Complex; D002446:Celiac Disease / Q000150:complications*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D019281:Dimerization; D006801:Humans; D016399:Lymphoma, T-Cell / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D055503:Protein Multimerization; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000172:deficiency*; D011948:Receptors, Antigen, T-Cell
chemical_list: D017252:CD3 Complex; C452842:CD3 antigen, gamma chain; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011948:Receptors, Antigen, T-Cell