title: Healthy HLA-DQ2.5+ Subjects Lack Regulatory and Memory T Cells Specific for Immunodominant Gluten Epitopes of Celiac Disease.
abstract: 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.
authors.affiliation: Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital, 0372 Oslo, Norway; and asbjorn.christophersen@rr-research.no.
authors.forename: Asbjørn
authors.initials: A
authors.lastname: Christophersen
authors.affiliation: Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital, 0372 Oslo, Norway; and.
authors.forename: Louise F
authors.initials: LF
authors.lastname: Risnes
authors.affiliation: Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital, 0372 Oslo, Norway; and.
authors.forename: Elin
authors.initials: E
authors.lastname: Bergseng
authors.affiliation: Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital, 0372 Oslo, Norway; and Department of Gastroenterology, Oslo University Hospital-Rikshospitalet, 0372 Oslo, Norway.
authors.forename: Knut E A
authors.initials: KE
authors.lastname: Lundin
authors.affiliation: Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital, 0372 Oslo, Norway; and.
authors.forename: Ludvig M
authors.initials: LM
authors.lastname: Sollid
authors.affiliation: Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital, 0372 Oslo, Norway; and.
authors.forename: Shuo-Wang
authors.initials: SW
authors.lastname: Qiao
mesh_terms: D002446:Celiac Disease / Q000276:immunology*; D002460:Cell Line; D049109:Cell Proliferation; D060966:Clonal Selection, Antigen-Mediated; D016207:Cytokines / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005983:Glutens / Q000276:immunology; D006683:HLA-DQ Antigens / Q000378:metabolism*; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D007156:Immunologic Memory; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; D016056:Immunodominant Epitopes; D053645:Interleukin-2 Receptor alpha Subunit; D005983:Glutens