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Prevalence of Newly Generated Naive Regulatory T Cells (T_reg) Is Critical for T_reg Suppressive Function and Determines T_reg Dysfunction in Multiple Sclerosis¹

Jürgen Haas^*, Benedikt Fritzsching^*,, Petra Trübswetter^*, Mirjam Korporal^*, Linda Milkova^*, Brigitte Fritz^*, Diana Vobis, Peter H. Krammer, Elisabeth Suri-Payer and Brigitte Wildemann^2,*

^* Division of Molecular Neuroimmunology, Department of Neurology, University of Heidelberg, Heidelberg, Germany; and Division of Immunogenetics/Tumorimmunology Program, Deutsches Krebsforschungszentrum, Heidelberg, Germany

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 V 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Gemeinnützige Hertie-Stiftung (1.01.1/04/003), Deutsche Forschungsgemeinschaft (Sonderforschungsbereich (SFB) 405, 5H and SFB 571, B7), the Young Investigator Award from the Faculty of Medicine, University of Heidelberg (to B.F.), and Serono Deutschland GmbH.

² Address correspondence and reprint requests to Dr. Brigitte Wildemann, Division of Molecular Neuroimmunology, Department of Neurology, University of Heidelberg, INF 350, Heidelberg, Germany. E-mail address: brigitte_wildemann{at}med.uni-heidelberg.de

³ Abbreviations used in this paper: T_reg, regulatory T cell; CS, complexity score; GA, glatiramer acetate; HC, healthy control; MS, multiple sclerosis; RRMS, relapsing remitting MS; RTE, recent thymic emigrant; T_eff, effector T cell; TREC, TCR excision circle.

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