Prevalence of newly generated naive regulatory T cells (Treg) is critical for Treg suppressive function and determines Treg dysfunction in multiple sclerosis

The suppressive function of regulatory T cells (T-reg) is impaired in multiple sclerosis (MS) patients. The mechanism underlying the Treg functional defect is unknown. T-reg mature in the thymus and the majority of cells circulating in the periphery rapidly adopt a memory phenotype. Because our own previous findings suggest that the thymic output of T cells is impaired in MS, we hypothesized that an altered T-reg generation may contribute to the suppressive deficiency. We therefore determined the role of T-reg that enter the circulation as recent thymic emigrants (RTE) and, unlike their CD45RO(+) memory counterparts, express CD31 as typical surface marker. We show that the numbers of CD31(+)-coexpressing CD4(+)CD25(+)CD45RA(+)CD45RO-FOXP3(+) T-reg (RTE-T-g) within peripheral blood decline with age and are significantly reduced in MS patients. The reduced de novo generation of RTE-T-reg is compensated by higher proportions of memory T-reg, resulting in a stable cell count of the total T-reg population. Depletion of CD31(+) cells from T-reg diminishes the suppressive capacity of donor but not patient T-reg and neutralizes the difference in inhibitory potencies between the two groups. Overall, there was a clear correlation between T-reg-mediated suppression and the prevalence of RTE-T-reg, indicating that CD31-expressing naive T-reg contribute to the functional properties of the entire T-reg population. Furthermore, patient-derived T-reg, but not healthy T-reg, exhibit a contracted TCR V beta repertoire. These observations ggest that a shift in the homeostatic composition of T-reg subsets related to a reduced thymic-dependent de novo generation of RTE-T-reg with a compensatory expansion of memory Tmg may contribute to the Treg defect associated with MS.