Patients with relapsing-remitting multiple sclerosis have normal Treg function when cells expressing IL-7 receptor α-chain are excluded from the analysis

Michel, Laure; Berthelot, Laureline; Pettré, Ségolène; Wiertlewski, Sandrine; Lefrère, Fabienne; Braudeau, Cécile; Brouard, Sophie; Soulillou, Jean‐Paul; Laplaud, David‐Axel

doi:10.1172/jci35365

Cited by 75 publications

(105 citation statements)

References 40 publications

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“…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.…”

Section: Foxp3supporting

confidence: 55%

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

et al. 2010

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Migration of immune cells characterizes inflammation and plays a key role in autoimmune diseases such as MS. CD41 Foxp31 regulatory T cells (Treg) have the potential to dampen immune responses but show functional impairment in patients with MS. We here show that murine Treg exhibit higher constitutive cell motility in horizontal migration on laminin, surpass non-Treg in transwell assays through microporous membranes as well as across primary brain endothelium and are present in the naïve CNS to a significantly higher extent compared to spleen, lymph nodes and blood. Likewise, human Treg from healthy donors significantly exceed non-Treg in migratory rates across primary human brain endothelium. Finally, we investigated whether the propensity to migrate is impaired as a feature of autoimmunity and therefore tested patients with MS. Treg from patients with stable relapsing-remitting MS show significantly impaired migratory capacity under non-inflammatory conditions compared to healthy donors. We hypothesize that the enhanced propensity to migrate is a feature of Treg that allows for an equilibrium in parenchymal immune surveillance, e.g. of the CNS. Impaired Treg migration across the intact blood-brain barrier, as observed for Treg from patients with MS, indicates a broader functional deficiency hypothetically contributing to early CNS lesion development or phases of MS remissions.Key words: Blood-brain barrier . Brain microvascular endothelial cells . Migration . MS . Regulatory T cells Supporting Information available online IntroductionNaturally occurring CD4 1 Foxp3 1 regulatory T cells (Treg) are essential mediators of peripheral immune tolerance, regulating inflammation in the context of infection, autoimmunity, neoplasia and transplant rejection [1]. In addition to balancing immunity within lymphoid tissues, Treg enter non-lymphoid target sites of inflammation, exerting their anti-inflammatory function there [2][3][4][5]. First, regulatory as well as effector T-cell subsets have to undergo a non-lymphoid homing receptor switch after entering secondary lymphoid tissue [6]. Upon encountering specific antigens provided by dendritic cells in the T-cell area [7], the lymphocytes acquire an activated phenotype, expressing distinct surface markers of non-lymphoid homing Ã These authors contributed equally to this work. We here combined various murine and human models quantifying transmigratory capacity and locomotion to determine how constitutive, innate Treg motility translates into diapedesis across CNS endothelium. Results Murine Treg exhibit enhanced migratory capacity in vitro and in vivoWe first characterized lymph node-derived regulatory and nonregulatory T-cell subsets with regard to their expression of surface markers indicative for adhesion, migration and activation. In line with previous results for CCR6 [17], murine Treg consistently showed a significantly higher expression for all inspected markers apart from CCR7, where the higher expression was not significant (p 5 0.126), and a significantly lower e...

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Section: Foxp3supporting

confidence: 55%

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

et al. 2010

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“…However, Treg cells purified using this method may be contaminated with activated T cells that interfere with the suppression assay (33). By using the surface CD4 ϩ CD127 low CD25 ϩ phenotype to isolate the Treg cell population, we were able to assess the functional capacity of pure Treg cells (23).…”

Section: Whereas Cd4mentioning

confidence: 99%

Systemic Increase in the Ratio between Foxp3+ and IL-17-Producing CD4+ T Cells in Healthy Pregnancy but Not in Preeclampsia

Santner-Nanan¹,

Peek

Khanam³

et al. 2009

The Journal of Immunology

393

318

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Preeclampsia is the leading cause of morbidity and mortality in pregnancy. Although the etiology of preeclampsia is still unclear, it is believed to involve rejection of the fetus, possibly due to an imbalance between regulatory (Treg) and effector T cells. To test this, we compared the frequencies of circulating CD4+ T cells expressing Foxp3, IFN-γ, IL-10, or IL-17 at the end of the third trimester of healthy and preeclamptic pregnancies. The size of the Treg cell compartment, defined by the frequency of CD4+CD25high, CD4+CD127lowCD25+, and CD4+Foxp3+ cells was significantly higher in normal compared with preeclamptic pregnancies. CD4+CD25high and CD4+CD127lowCD25+ populations in preeclampsia were not significantly different from those in nonpregnant controls, whereas CD4+Foxp3+ cells numbersre slightly lower in preeclampsia. The suppressive activity of ex vivo-sorted CD4+CD127lowCD25+ Treg cells was not significantly different between the three study groups. The percentage of CD4+IL-17-producing T cells decreased significantly in healthy compared with preeclamptic pregnancies and nonpregnant controls, whereas CD4+IL-10- and CD4+IFN-γ-producing cells remained unchanged. Consequently, the ratio of Foxp3+ Treg to IL-17-expressing CD4+ T cells was significantly increased in healthy but not in preeclamptic pregnancies. Thus, preeclampsia is associated with the absence of normal systemic skewing away from IL-17 production toward Foxp3+ expression. Finally, preeclamptic women had significantly higher levels of soluble endoglin, an inhibitor of TGF-β receptor signaling, which may bias toward IL-17 production. These results suggest that homeostasis between regulatory and proinflammatory CD4+ T cells might be pivotal for the semiallogeneic fetus to be tolerated within the maternal environment.

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“…However, it was also shown that CD4 + CD25 hi CD127 lo T cells of patients with multiple sclerosis had normal suppressive activity in polycloncal T cell activation assays (Michel et al, 2008), suggesting that the characterization of the Treg population, as well as the method to measure suppression, may influence the outcome. The mechanisms for Treg defects in patients with multiple sclerosis are unknown.…”

Section: Introductionmentioning

confidence: 99%

MicroRNAs targeting TGFβ signalling underlie the regulatory T cell defect in multiple sclerosis

Severin

Lee

Liu

et al. 2016

Brain

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Patients with relapsing-remitting multiple sclerosis have normal Treg function when cells expressing IL-7 receptor α-chain are excluded from the analysis

Cited by 75 publications

References 40 publications

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

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

Systemic Increase in the Ratio between Foxp3+ and IL-17-Producing CD4+ T Cells in Healthy Pregnancy but Not in Preeclampsia

MicroRNAs targeting TGFβ signalling underlie the regulatory T cell defect in multiple sclerosis

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