Natural naive CD4+ CD25+ CD127low regulatory T cell (Treg) development and function are disturbed in multiple sclerosis patients: recovery of memory Treg …

K Venken, N Hellings, T Broekmans… - The Journal of …, 2008 - journals.aai.org
K Venken, N Hellings, T Broekmans, K Hensen, JL Rummens, P Stinissen
The Journal of Immunology, 2008journals.aai.org
Patients with relapsing-remitting multiple sclerosis (RR-MS) show a suboptimal CD4+
CD25+ regulatory T cell (Treg) function, whereas no Treg alterations are observed in
secondary progressive MS (SP-MS) patients. To clarify the difference in Treg activity
between early and chronic disease stages in MS, we analyzed the functional capacity and
homeostatic parameters of naive CD4+ CD25+ CD127 low CD45RA+ Tregs (nTregs) and
their memory counterparts CD4+ CD25+ CD127 low CD45RO+ Tregs (mTregs) in untreated …
Abstract
Patients with relapsing-remitting multiple sclerosis (RR-MS) show a suboptimal CD4+ CD25+ regulatory T cell (Treg) function, whereas no Treg alterations are observed in secondary progressive MS (SP-MS) patients. To clarify the difference in Treg activity between early and chronic disease stages in MS, we analyzed the functional capacity and homeostatic parameters of naive CD4+ CD25+ CD127 low CD45RA+ Tregs (nTregs) and their memory counterparts CD4+ CD25+ CD127 low CD45RO+ Tregs (mTregs) in untreated MS patients and healthy controls. Interestingly, whereas the suppressive capacity of FACS-sorted nTregs was impaired in both early and chronic MS patients, only the latter group showed a restored mTreg function. Consistent with this observation, chronic MS patients had increased numbers of mTregs as compared with age-matched early MS patients, whereas nTreg frequencies did not differ significantly. TCR excision circle numbers were reduced in nTregs of early MS patients, suggestive of a diminished nTreg thymic output. Moreover, a decreased number of CD31+ mTregs were observed in early vs chronic MS patients, indicating that inflammatory processes drive the homeostatic turnover of mTregs during the early disease stage. Additionally, early MS patients showed a more restricted nTreg and mTreg TCR BV gene profile as compared with healthy controls and chronic MS patients. Finally, analysis of IFN-β and glatiramer acetate-treated MS patients showed that these immunomodulatory drugs modify nTreg homeostasis. Taken together, this study provides strong evidence for a disturbed thymic nTreg development and function in MS patients. Moreover, memory Treg but not naive Treg homeostasis recovers during disease progression.
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