An even more pronounced age-inappropriate decline of newly generated T cells associates with rheumatoid arthritis suggesting that
premature decline of thymic activity might be a common feature in these and other autoimmune disorders 7. The cytokine interleukin-7 (IL-7), a pleiotropic hematopoietic growth factor, is known to stimulate the thymus and to promote the differentiation and maintenance of naïve T cells including Treg 8–10. Signaling from IL-7 occurs through the heterodimeric IL-7 receptor (IL-7R), which is expressed on lymphocytes and consists of the α-chain subunit (IL-7Rα) and the common cytokine γ-chain. The importance of this pathway for naïve T-cell homeostasis is underlined by several recent studies showing that expression levels of membrane-bound IL-7Rα Selleckchem Decitabine (CD127) on conventional CD4+ T cells correlate
with frequencies of recent thymic emigrant (RTE)-CD4+ T cells in healthy individuals and HIV-infected patients as well as in patients with MS 11, 12. IL-7Rα is also a component of the receptor for thymic stromal lymphopoietin (TSLP). The secretion of TSLP by Hassall’s corpuscles, structures composed of epithelial cells in the thymic medulla, has been demonstrated to condition CD11c+ myeloid dendritic cells (MDCs) to induce the differentiation of thymocytes into Treg 13. Accordingly, signals from the IL-7 receptor are required for Treg development Rapamycin supplier as shown in IL-7Rα knockout mice 14. Of note, a single nucleotide polymorphism (rs6897932-SNP) within the gene encoding the IL-7Rα chain (IL-7RA) has shown genetic association with human
autoimmunity and was found to be associated with MS, type 1 diabetes and chronic inflammatory arthropathies 15–19. 3-mercaptopyruvate sulfurtransferase This SNP causes a change from threonine to isoleucine at amino acid position 244 that modifies the ratio of membrane-bound to soluble IL-7R 15, 20. In this study, we attempted to decipher in more detail the impact of IL-7/IL-7R signaling components on Treg homeostasis and Treg-suppressive function. We used peripheral blood and plasma samples from 56 treatment-naïve patients with relapsing remitting MS (RRMS) and 33 healthy individuals (HC) to analyze IL-7Rα-expression on total CD4+CD25−/lowCD127+FOXP3− conventional T cells (Tconv) and Tconv subsets together with plasma concentrations of soluble IL-7Rα (sIL-7Rα) and IL-7 as well as genotype screening for rs6897932-SNP. In parallel, we determined frequencies, phenotypes and suppressive activities of donor and patient-derived Treg. Treg obtained from both cohorts were further characterized as to quantities of cells harboring two T-cell receptor (TCR) Vα chains. Cells expressing TCRs with dual specificity on their surface are enriched in the Treg compartment and as this feature is acquired during T-cell maturation in the thymus, their proportions among total Treg should roughly correlate with the natural Treg lineage 21.