Abstract
Chronic inflammation of the small intestine in celiac disease is driven by activation of CD4+ T cells that recognize gluten peptides presented by disease-associated HLA-DQ molecules. We have performed direct cell cloning of duodenal biopsies from five untreated and one refractory celiac disease patients, and three non-celiac disease control subjects in order to assess, in an unbiased fashion, the frequency of gluten-reactive T cells in the disease-affected tissue as well as the antigen fine specificity of the responding T cells. From the biopsies of active disease lesions of five patients, 19 T-cell clones were found to be gluten-reactive out of total 1,379 clones tested. This gave an average of 1.4% (range 0.7% - 1.9%) of gluten-reactive T cells in lamina propria of active celiac lesions. Interestingly, also the patient with refractory celiac disease had gluten-reactive T cell clones in the lamina propria (5/273; 1.8%). In comparison, we found no gluten-reactive T cells in any of the total 984 T-cell clones screened from biopsies from three disease control donors. Around two thirds of the gluten-reactive clones were reactive to a panel of peptides representing known gluten T-cell epitopes, of which two thirds were reactive to the immunodominant DQ2.5-glia-α1/DQ2.5-glia-α2 and DQ2.5-glia-ω1/DQ2.5-glia-ω2 epitopes. This study shows that gluten-reactive T cells in the inflamed duodenal tissue are prevalent in the active disease lesion, and that many of these T cells are reactive to T-cell epitopes that are not yet characterized. Knowledge of the prevalence and epitope specificity of gluten-specific T cells is a prerequisite for therapeutic efforts that target disease-specific T cells in celiac disease.
Highlights
Celiac disease is a chronic inflammatory disease of the small intestine elicited by T-cell mediated immune response to dietary gluten
After 10 days in vitro culture in the presence of PHA, IL-2 and IL-15, we found wells containing growing T cells in frequencies that were directly correlated with the seeding concentration of unfractionated lamina propria cells (Table 2)
Gluten-reactive T cells are a hallmark of celiac disease
Summary
Celiac disease is a chronic inflammatory disease of the small intestine elicited by T-cell mediated immune response to dietary gluten. The disease-associated HLA-molecules present gluten to CD4+ T cells. 27 distinct HLA-DQ2.5restricted T-cell epitopes have been characterized from gluten and related proteins such as hordein (barley), secalin (rye) and avenin (oat) [1]. CD4+ T cells reactive to these epitopes can only be found in the intestinal tissue of celiac disease patients, and not in controls including non-celiac gluten-intolerant patients [2, 3]. All HLA-DQ2.5-restricted gluten T-cell epitopes contain one or several glutamic residues within the 9-mer core HLA-binding region. Native gluten has few glutamic acid residues, but contains over 35% glutamine residues [4]. Certain glutamine residues in the native gluten can be post-translationally modified into glutamic acid residues by the action of transglutaminase 2 (TG2), in a reaction known as deamidation [5]. The negatively charged glutamic acid residues increase the binding affinity of gluten peptides to HLA-DQ2.5 [6]
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