Healthy HLA-DQ2.5+ Subjects Lack Regulatory and Memory T Cells Specific for Immunodominant Gluten Epitopes of Celiac Disease

• Published in: The Journal of immunology (1950) Vol. 196; no. 6; pp. 2819 - 2826
• Main Authors: Christophersen, Asbjørn, Risnes, Louise F, Bergseng, Elin, Lundin, Knut E A, Sollid, Ludvig M, Qiao, Shuo-Wang
• Format: Journal Article
• Language: English
• Published: United States 15.03.2016
• Subjects: Celiac Disease - immunology; Cell Line; Cell Proliferation; Clonal Selection, Antigen-Mediated; Cytokines - metabolism; Forkhead Transcription Factors - metabolism; Glutens - immunology; HLA-DQ Antigens - metabolism; Humans; Immunodominant Epitopes - immunology; Immunologic Memory; Interleukin-2 Receptor alpha Subunit - metabolism; Lymphocyte Activation; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Regulatory - immunology
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1501152

Celiac disease (CD) is an HLA-associated disorder characterized by a harmful T cell response to dietary gluten. It is not understood why most individuals who carry CD-associated HLA molecules, such as HLA-DQ2.5, do not develop CD despite continuous gluten exposure. In this study, we have used tetramers of HLA-DQ2.5 bound with immunodominant gluten epitopes to explore whether HLA-DQ2.5+ healthy individuals mount a specific CD4+ T cell response to gluten. We found that gluten tetramer-binding memory cells were rare in blood of healthy individuals. These cells showed lower tetramer-binding intensity and no signs of biased TCR usage compared with gluten tetramer-binding memory T cells from patients. After sorting and in vitro expansion, only 18% of the tetramer-binding memory cells from healthy subjects versus 79% in CD patients were gluten-reactive upon tetramer restaining. Further, T cell clones of tetramer-sorted memory cells of healthy individuals showed lower gluten-specific proliferative responses compared with those of CD patients, indicating that tetramer-binding memory cells in healthy control subjects may be cross-reactive T cells. In duodenal biopsy specimens of healthy control subjects, CD4+ T cells were determined not to be gluten reactive. Finally, gluten tetramer-binding cells of healthy individuals did not coexpress regulatory T cell markers (Foxp3+ CD25+) and cultured T cell clones did not express a cytokine profile that indicated immune-dampening properties. The results demonstrate that healthy HLA-DQ2.5+ individuals do not mount a T cell response to immunodominant gluten epitopes of CD.