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

IntroductionCeliac disease (CD) is an inflammatory disorder of the small intestine caused by a dysregulated immune response to ingested wheat gluten, which typically leads to villous atrophy and increased numbers of intraepithelial lymphocytes (IELs) in the intestinal mucosa. Whereas most patients recover on a gluten-free diet, a small proportion of patients fails to improve and develops a condition called refractory celiac disease (RCD). RCD is characterized by persisting or recurring villous atrophy with crypt hyperplasia and an increase of IELs despite a gluten-free diet. Two types of RCD are currently recognized: RCD I, without aberrant IELs; and RCD II, with aberrant IELs. [1][2][3] The aberrant IELs in RCD II lack CD3, CD4, CD8, and the T-cell receptor (TCR) on the surface but express CD3 intracellularly and display monoclonal TCR-␥ gene rearrangement. 2,4,5 Furthermore, it has been shown that interleukin-15 (IL-15) is up-regulated in the lamina propria and epithelial cells of RCD patients, which induces growth and activation of these clonal IELs. 6,7 Because an expansion of IELs under the influence of IL-15 may eventually give rise to overt enteropathy-associated T-cell lymphoma (EATL), the presence of such a clonal IEL population is thought to be a premalignant condition. 1,2,6,8 It is not known what drives lymphoma development and the associated loss of TCR expression in RCD II. In the present study, we report the isolation of a cell line from a duodenal biopsy of a patient with RCD II. This cell line has the characteristic CD4 Ϫ , CD8 Ϫ , intracellular CD3⑀ ϩ , surface TCR-CD3 Ϫ phenotype of RCD II-associated IELs and proliferates in the presence of IL-15. In addition, these IELs express CD30 on the cell surface, as is typically seen in EATL. 9 We have used this cell line and subunit-specific antibodies to analyze the expression and assembly of the TCR and CD3 subunits. The results indicate that, whereas all TCR-CD3 subunits were present intracellularly, proper assembly of the TCR-␣␤ dimer was defective. Functional cell surface expression of the complex could be restored by the introduction of an exogenous TCR-␤ chain. A similar analysis of cell lines isolated from 2 additional RCD II patients indicated defects in the synthesis of the TCR chains. Defective synthesis or defective association of TCR chains thus causes loss of functional surface TCR-CD3 expression on IELs in RCD II, a process that is probably important in escape from immune regulation and progression into EATL. Methods Patient historiesPatient 1 (P1) was typed as human leukocyte antigen (HLA)-A1/A2, -B8, -Cw7/Cw12, DR3/7, DQ2 and developed CD at the age of 51 years. At age 67, RCD type II with aberrant IELs was diagnosed. Until the present study, no EATL has developed. 10 Patient 2 (P2) was typed as HLA-A3/32, -B8, -Cw7, DR3, DQ2 and patient 3 (P3) as HLA-A1, -B8, -Cw7, DR3, DQ2. The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and ...

CD4 T-cell cytokines synergize to induce proliferation of malignant and nonmalignant innate intraepithelial lymphocytes

“…To this end, cell-free supernatants were harvested from glutenspecific CD4 + T-cell clones activated by gluten peptide-loaded, HLA-DQ2 + peripheral blood mononuclear cells (PBMCs). These CD4 + T-cell supernatants were subsequently incubated with Lin − IEL lines from RCDII patients (27,28), and Lin − IEL proliferation was determined by measuring 3 H-thymidine uptake. Three out of four Lin − IEL lines proliferated in response to CD4 + T-cell supernatant, two to a similar degree as an optimal dose of IL-15 ( Fig.…”

“…Malignant RCDII Lin − IEL lines and gluten-specific CD4 + T-cell lines and clones were isolated and cultured as described previously (25,27,62). To generate CD4 + supernatants for Lin − IEL stimulation, the clones were activated via their T-cell receptors, by stimulation with either gluten peptide-loaded PBMCs or plate-bound antibodies to CD3 and CD28.…”

New developments in the pathology of malignant lymphoma. A review of the literature published from August 2013 to December 2013

“…Using a cell line derived from such a lymphoma, Tjon et al [50] were able to determine the mechanism responsible for this: defective assembly or association of T-cell receptor chains. The finding was confirmed in two other patients.…”

DNAM-1 Mediates Epithelial Cell-Specific Cytotoxicity of Aberrant Intraepithelial Lymphocyte Lines from Refractory Celiac Disease Type II Patients

“…They grow in an IL-15-dependent fashion (13), which is of interest, as IL-15 is known to be overexpressed in the intestine of patients with RCD and lymphoma (5). Furthermore, they express granzyme B (Supplemental Fig.…”

“…RCD cell lines P1, P2, and P3 were isolated from duodenal biopsies of three RCD II patients as previously described (13 + were cultured in IMDM with 10% NHS containing 10 ng/ml IL-15 and restimulated every 2 wk. Fifteen additional cell lines were isolated from biopsies of RCD II patients following the method for RCD cell lines P1, P2, and P3.…”