Natural naive regulatory T cell development and function are disturbed in multiple sclerosis patients

• Published in: Multiple sclerosis 2008-09, Vol.14, p.S135-S135
• Main Authors: Venken, K, Hellings, N, Hensen, K, Rummens, J-L
• Format: Article
• Language: English
• ISSN: 1352-4585

Background: Myelin-reactive T cells may play a pathogenic role in multiple sclerosis (MS). We and others have shown that regulatory CD4+CD25+FOXP3+CD127low T cells (Tregs) are functionally disturbed in relapsing-remitting (RR) MS patients but not in secondary progressive (SP) MS patients. Objective: To clarify this difference in Treg activity between early and chronic disease stages in MS. Methods: We analyzed the functional capacity and homeostatic parameters of (precursor) naive Tregs (nTregs) and memory Tregs (mTregs). We also measured myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) proliferative responses of CD4total T cells (including Tregs), naive (CD45RAhigh) and memory (CD45RA-) CD4+CD25-CD127high T cells (no Tregs included) of RRMS and SPMS patients and healthy controls (HC) by means of a CFSE dilution assay and measured cytokine production of the myelin-reactive T cells. Results: The suppressive capacity of FACS-sorted nTregs was impaired in both early and chronic MS patients, whereas only the latter group showed a restored mTreg function. Chronic MS patients had increased numbers of mTregs as compared with age-matched early MS patients, whereas nTreg frequencies did not differ. T cell receptor excision circle (TREC) numbers were reduced in nTregs of early MS patients, indicating a diminished nTreg thymic output. MBP and MOG proliferative responses of CD4total T cells, but not of Treg-depleted naive and memory CD4+CD25-CD127high T cells, were significantly higher in RRMS patients as compared with HC and SPMS patients. A significantly higher proportion of myelin reactive memory T cells from MS patients as compared with HC produced IL-17. Conclusions: These data provide evidence for a disturbed thymic nTreg development and function in early MS disease stage. This may play a role in the peripheral activation of myelin antigen-reactive T cells leading to central nervous system pathology. Future therapeutic immune interventions for MS may focus on an early restoration of Treg function and suppression of pathogenic myelin-reactive Th17 cells.