The dynamic co-evolution of memory and regulatory CD4+ T cells in the periphery

Department of Immunology and Molecular Pathology, Division of Infection and Immunity, Windeyer Institute of Medical Sciences, University College London, London W1T 4JF, UK.
Nature reviews. Immunology (Impact Factor: 34.99). 04/2007; 7(3):231-7. DOI: 10.1038/nri2037
Source: PubMed


Whereas memory T cells are required to maintain immunity, regulatory T cells have to keep the immune system in check to prevent excessive inflammation and/or autoimmunity. Both cell types must be present during the lifetime of the organism. However, it is not clear whether both subsets are regulated in tandem or independently of each other, especially because thymic involution severely restricts the production of T-cell populations during ageing. In this Opinion article, we discuss recent evidence in both mice and humans that supports the hypothesis that some CD4(+)CD25(+)FOXP3(+)regulatory T cells can differentiate from rapidly proliferating memory T cells in the periphery.

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Available from: Milica Vukmanovic-Stejic, Mar 16, 2015
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    • "Cytokine IL-17 has proinflammatory activity and characterizes the type-Th17 response [23] [24]; it has been described to induce inflammation in autoimmune diseases and acute graft rejection. In contrast, Treg cells induce immunoregulation and tolerance by inhibiting cytokine production and proliferation in T CD4 + and CD8 + cells, immunoglobulin production by B cells, the cytotoxic activity of natural-killer cells, and the maturation of dendritic cells, which results in tolerance induction [18] [25] [26]. "
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    ABSTRACT: The purpose of this study was to review the literature regarding the action of the cytokines interleukin 10 (IL-10) and tumor necrosis factor-alpha (TNF-α) in pregnancy and to emphasize the factors that are of interest to clinical obstetrics. The literature highlights several actions of IL-10 and TNF-α during pregnancy. The actions of these cytokines seem to be antagonistic and dependent on the balance between them, which is orchestrated by the specific immunosuppressive action of IL-10. TNF-α has a characteristic inflammatory action, and it is an additional diabetogenic factor in pregnancy. The loss of the control of the production of these cytokines, with increase of TNF-α, is related to the risk for developing obstetric complications, particularly recurrent fetal loss, gestational diabetes mellitus, hypertensive syndromes, and fetal growth restriction. However, study results are controversial and are not clearly defined. These issues are attributed to the heterogeneity of the studies, particularly regarding their sample sizes and sources, the evaluation methods, and the multiplicity of factors and conditions that influence cytokine production. These questions are fundamental and should be addressed in future investigations to obtain more consistent results that can be applied to obstetric practice.
    ISRN obstetrics and gynecology 02/2012; 2012:230742. DOI:10.5402/2012/230742
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    • "This result indicated the possibility that impaired thymic export contributes to Treg cell defects in this patient population. However, nTreg cells can proliferate after thymic output while retaining their naïve phenotype [37]. CD31 has been used as a direct marker of thymic output and enabled the discrimination of recent thymic emigrant (RTE) Treg cells from peripherally expanded nTreg cells [38]. "
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    ABSTRACT: Animal studies suggest that regulatory T (T(reg)) cells play a beneficial role in ventricular remodeling and our previous data have demonstrated defects of T(reg) cells in patients with chronic heart failure (CHF). However, the mechanisms behind T(reg-)cell defects remained unknown. We here sought to elucidate the mechanism of T(reg-)cell defects in CHF patients. We performed flow cytometry analysis and demonstrated reduced numbers of peripheral blood CD4(+)CD25(+)FOXP3(+)CD45RO(-)CD45RA(+) naïve T(reg) (nT(reg)) cells and CD4(+)CD25(+)FOXP3(+)CD45RO(+)CD45RA(-) memory T(reg) (mT(reg)) cells in CHF patients as compared with non-CHF controls. Moreover, the nT(reg)/mT(reg) ratio (p<0.01), CD4(+)CD25(+)FOXP3(+)CD45RO(-) CD45RA(+)CD31(+) recent thymic emigrant T(reg) cell (RTE-T(reg)) frequency (p<0.01), and T-cell receptor excision circle levels in T(reg) cells (p<0.01) were lower in CHF patients than in non-CHF controls. Combined annexin-V and 7-AAD staining showed that peripheral T(reg) cells from CHF patients exhibited increased spontaneous apoptosis and were more prone to interleukin (IL)-2 deprivation- and CD95 ligand-mediated apoptosis than those from non-CHF individuals. Furthermore, analyses by both flow cytometry and real-time polymerase chain reaction showed that T(reg)-cell frequency in the mediastinal lymph nodes or Foxp3 expression in hearts of CHF patients was no higher than that of the non-CHF controls. Our data suggested that the T(reg)-cell defects of CHF patients were likely caused by decreased thymic output of nascent T(reg) cells and increased susceptibility to apoptosis in the periphery.
    PLoS ONE 09/2011; 6(9):e24272. DOI:10.1371/journal.pone.0024272 · 3.23 Impact Factor
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    • "Regulatory T cells are thought to derive either as a separate lineage from the thymus that are present at birth and often termed natural regulatory T cells or, are derived from previously activated T cells that after a number of cell divisions either gain, or can be induced, to have regulatory functions. These cells are often termed adaptive or induced regulatory T cells (Akbar et al., 2007). Previous work by our group and others has shown that in children with ASD there is a decrease in the regulatory cytokine TGFb1 that is produced by different types of regulatory T cells, and decreases in the frequencies of the CD3 + IL-10 + T cell subset that may reflect changes in the ability of specific types of regulatory T cells to control immune responses in ASD (Ashwood et al., 2004, 2006, 2008; Jyonouchi et al., 2001; Molloy et al., 2005; Okada et al., 2007). "
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    ABSTRACT: Autism spectrum disorders (ASD) are characterized by impairment in social interactions, communication deficits, and restricted repetitive interests and behaviors. A potential etiologic role for immune dysfunction in ASD has been suggested. Dynamic adaptive cellular immune function was investigated in 66 children with a confirmed diagnosis of ASD and 73 confirmed typically developing (TD) controls 2-5 years-of-age. In vitro stimulation of peripheral blood mononuclear cells with PHA and tetanus was used to compare group-associated cellular responses. The production of GM-CSF, TNFα, and IL-13 were significantly increased whereas IL-12p40 was decreased following PHA stimulation in ASD relative to TD controls. Induced cytokine production was associated with altered behaviors in ASD children such that increased pro-inflammatory or T(H)1 cytokines were associated with greater impairments in core features of ASD as well as aberrant behaviors. In contrast, production of GM-CSF and T(H)2 cytokines were associated with better cognitive and adaptive function. Following stimulation, the frequency of CD3(+), CD4(+) and CD8(+) T cells expressing activation markers CD134 and CD25 but not CD69, HLA-DR or CD137 were significantly reduced in ASD, and suggests an altered activation profile for T cells in ASD. Overall these data indicate significantly altered adaptive cellular immune function in children with ASD that may reflect dysfunctional immune activation, along with evidence that these perturbations may be linked to disturbances in behavior and developmental functioning. Further longitudinal analyzes of cellular immunity profiles would delineate the relationship between immune dysfunction and the progression of behavioral and developmental changes throughout the course of this disorder.
    Brain Behavior and Immunity 07/2011; 25(5):840-9. DOI:10.1016/j.bbi.2010.09.002 · 5.89 Impact Factor
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