Natural Naive CD4+CD25+CD127low Regulatory T Cell (Treg) Development and Function Are Disturbed in Multiple Sclerosis Patients: Recovery of Memory Treg Homeostasis during Disease Progression

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+CD127lowCD45RA+ Tregs (nTregs) and their memory counterparts CD4+CD25+CD127lowCD45RO+ 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.

Haplotype 4 of the multiple sclerosis-associated interleukin-7 receptor alpha gene influences the frequency of recent thymic emigrants

“…All analyses were performed on untreated MS patients, because it was reported that treatment strongly influences Treg function. 14 …”

“…Also, two independent studies of Venken et al 14 and Haas et al 15 showed that CD31 (PECAM-1) expressing naive Tregs are significantly reduced in the peripheral blood of MS patients. 14,15 CD31 is a 130 kDa transmembrane glycoprotein expressed by endothelial cells, platelets, monocytes, neutrophils and T cell subsets. It was further shown that this adhesion molecule is a marker for recent thymic emigrants (RTE), which are characterized by a high number of T cell receptor excision circles and a low number of cell divisions.…”

Activation of myelin reactive T cells in multiple sclerosis: A possible role for T cell degeneracy?

“…For example, given this relatively high frequency of potentially cross-reactive T cells in the periphery of these individuals, one would perhaps expect a much higher prevalence of MS. Clearly, several peripheral regulatory mechanisms are important in controlling these potentially pathogenic T cells. Several groups, including ours, recently reported impaired immune regulation by CD4CD25 hi regulatory T cells in the peripheral blood of MS patients [21,22]. This may explain why myelin specific T cells expand and persist in the blood of MS patients but not in healthy donors.…”

Regulatory T cells exhibit enhanced migratory characteristics, a feature impaired in patients with multiple sclerosis

“…Recent observations suggest that Treg should be equipped with a higher propensity to migrate [6] in order to efficiently suppress effector T cells at target sites of emerging inflammation, as they are hypoproliferative [8,9] and only form 6-10% of the whole CD4 1 T-cell subset. Reports on the accumulation of Treg within the murine CNS during EAE [3] and on containment of EAE relapses by CNS Treg [10,11] 15: p. 72) described the detection of low numbers of Treg in the CNS and in accordance with an earlier study elevated cell numbers in the cerebrospinal fluid of patients with MS [13]. Since increasing evidence supports an antiinflammatory role for Treg at parenchymal sites of inflammation [14], one could speculate that the repeatedly reported impairment in antiproliferative capacity of Treg found in patients with MS [15,16] is just one expression of a more thorough Treg dysfunction.…”

“…Reports on the accumulation of Treg within the murine CNS during EAE [3] and on containment of EAE relapses by CNS Treg [10,11] 15: p. 72) described the detection of low numbers of Treg in the CNS and in accordance with an earlier study elevated cell numbers in the cerebrospinal fluid of patients with MS [13]. Since increasing evidence supports an antiinflammatory role for Treg at parenchymal sites of inflammation [14], one could speculate that the repeatedly reported impairment in antiproliferative capacity of Treg found in patients with MS [15,16] is just one expression of a more thorough Treg dysfunction. Whether Treg migration to sites of active inflammation in the CNS of patients with MS is impaired has been elusive so far.…”