Differences in the risk of celiac disease associated with HLA-DQ2.5 or HLA-DQ2.2 are related to sustained gluten antigen presentation

Abstract

Celiac disease driven by an antigluten T cell response is strongly associated with the histocompatibility antigen HLA-DQ2.5 but is barely associated with HLA-DQ2.2. Yet these molecules have very similar peptide-binding motifs and both present gluten T cell epitopes. We found that DQ2.5(+) antigen-presenting cells (APCs) had greater stability of bound peptides and protracted gluten presentation relative to that of DQ2.2(+) cells. The improved ability of DQ2.5 to retain its peptide cargo can be ascribed to a polymorphism of DQalpha22 whereby DQ2.5 (tyrosine) can establish a hydrogen bond to the peptide main chain but DQ2.2 (phenylalanine) cannot. Our findings suggest that the kinetic stability of complexes of peptide and major histocompatibility complex (MHC) is of importance for the association of HLA with disease.

Dietary gluten triggers concomitant activation of CD4 + and CD8 + αβ T cells and γδ T cells in celiac disease

“…It is characterized by small intestinal mucosal injury and nutrient malabsorption in genetically susceptible individuals due to dietary gluten ingestion. CD4 + T cells bearing αβ T-cell receptors (TCRs) are critical in the pathogenesis of the disease, as it occurs almost exclusively in HLA-DQ2-or HLA-DQ8-positive individuals (1,2). CD-associated gluten peptide CD4 + T-cell epitopes have been discovered, and HLA-DQ2/8-restricted gluten-reactive CD4 + T cells have been identified in individuals with CD (3)(4)(5).…”

“…CD-associated gluten peptide CD4 + T-cell epitopes have been discovered, and HLA-DQ2/8-restricted gluten-reactive CD4 + T cells have been identified in individuals with CD (3)(4)(5). Nonetheless, no gluten-induced enteropathy is seen in humanized mouse models expressing HLA-DQ2 and a gluten-specific TCR (6, 7), suggesting that CD4 + T cells alone are unable to induce tissue damage in CD (1,2).…”

HLA-DQ Molecules as Affinity Matrix for Identification of Gluten T Cell Epitopes

“…7) were proven to make kinetically stable complexes with HLA. For DQ2.5-restricted gluten epitopes of CD, this feature has been demonstrated to be a common denominator and thus most likely a critical factor for establishment of the T cell response toward the epitopes (16). The outlined approach should be applicable for identifying epitopes underlying HLA association with disease.…”

“…Typically the gluten peptides that are recognized by T cells of CD patients are posttranslationally modified (13,14). The enzyme transglutaminase 2 (TG2) converts certain residues in gluten peptides from glutamine to glutamate and this deamidation process improves the ability of DQ2.5, DQ2.2, and DQ8 to bind and present the peptides to T cells (15)(16)(17).…”

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

“…This is explained by the fact that, in contrast to other HLA-DQ variants, HLA-DQ2.5 binds many different gluten peptides with high affinity and low off-rates, thereby allowing efficient induction of a broad gluten-specific CD4 + T-cell response (19,20). Indeed, HLA-DQ2.5-restricted gluten-specific CD4 + T cells can be isolated from the lamina propria of duodenal biopsy specimens from patients with CD, but not from individuals without CD (21).…”