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

J Haas, B Fritzsching, P Trubswetter… - The Journal of …, 2007 - journals.aai.org
J Haas, B Fritzsching, P Trubswetter, M Korporal, L Milkova, B Fritz, D Vobis, PH Krammer…
The Journal of immunology, 2007journals.aai.org
The suppressive function of regulatory T cells (T reg) is impaired in multiple sclerosis (MS)
patients. The mechanism underlying the T reg 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 …
Abstract
The suppressive function of regulatory T cells (T reg) is impaired in multiple sclerosis (MS) patients. The mechanism underlying the T reg 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 reg) 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 Vβ repertoire. These observations suggest 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 T reg may contribute to the T reg defect associated with MS.
journals.aai.org