Circulating gluten‐specific, but not CMV‐specific, CD39+ regulatory T cells have an oligoclonal TCR repertoire

• Published in: Clinical & translational immunology 2020, Vol.9 (1), p.e1096-n/a
• Main Authors: Cook, Laura, Munier, C Mee Ling, Seddiki, Nabila, Hardy, Melinda Y, Anderson, Robert P, Zaunders, John, Tye‐Din, Jason A, Kelleher, Anthony D, Bockel, David
• Format: Article
• Language: English
• Subjects: Antigens; Autoimmune diseases; Bias; Blood; CD25 antigen; CD4 antigen; CD4+ T cells; Celiac disease; Chronic infection; CMV; coeliac disease; Cytomegalovirus; Disease; Epitopes; Gluten; Histocompatibility antigen HLA; Immunity (Disease); Immunological tolerance; Immunoregulation; Lymphocytes; Lymphocytes T; Patients; Peptides; Population; regulatory T cells; Short Communication; Studies; T cell receptors; TCR repertoire; Tumor necrosis factor
• ISSN: 2050-0068; 2050-0068
• DOI: 10.1002/cti2.1096

Objectives Understanding the T cell receptor (TCR) repertoire of regulatory CD4+ T‐cell (Treg) populations is important for strategies aiming to re‐establish tolerance in autoimmune diseases. We studied circulating deamidated gluten‐epitope‐specific CD39+ Tregs in patients with coeliac disease following an oral gluten challenge, and we used cytomegalovirus (CMV)‐specific CD39+ Tregs from healthy controls as a comparator population. Methods We used the OX40 assay to isolate antigen‐specific Tregs by induced surface co‐expression of CD25, OX40 and CD39. RACE PCR amplification and Sanger sequencing of the TCR β chain were used to analyse repertoire diversity. Results We found that, following oral gluten challenge, circulating gluten‐specific CD39+ Tregs had an oligoclonal TCR repertoire that contained public clonotypes. Conversely, the TCR repertoire of CMV‐epitope‐specific CD39+ Tregs from healthy controls was polyclonal. Discussion These data indicate that a biased TCR repertoire is not inherent to CD39+ Tregs, and, in this case, is apparently driven by the HLA‐DQ2.5‐restricted deamidated gluten peptide in coeliac disease patients. Conclusion This is the first assessment of the TCR repertoire within circulating human Tregs specific for foreign antigen. These data enhance our understanding of antigen‐specific CD4+ responses in the settings of chronic inflammation and infection and may help guide immunomonitoring strategies for CD4+ T cell‐based therapies, particularly for coeliac disease. Coeliac disease results from a loss of tolerance toward dietary gluten driven by pathogenic CD4+ T cells. We have previously shown gluten‐specific CD39+ Tregs are functionally impaired in patients. Here we show this Treg population has an oligoclonal TCR repertoire; however, this is not a general feature of peripheral Tregs as responses to CMV peptides contained a polyclonal TCR repertoire.