Level of double negative T cells, which produce TGF-β and IL-10, predicts CD8 T-cell activation in primary HIV-1 infection

Institut Pasteur, Régulation des infections rétrovirales, Département de Virologie, Paris, France.
AIDS (Impact Factor: 5.55). 01/2012; 26(2):139–148. DOI: 10.1097/QAD.0b013e32834e1484


Objective: Persistent immune activation plays a central role in the pathogenesis of HIV disease. Besides natural regulatory T cells (nTregs), ‘double negative’ T cells shown to exhibit regulatory properties could be involved in the control of harmful immune activation. The aim of this study was to analyze, in patients with primary HIV infection (PHI), the relationship between CD4+CD25+CD127lowFoxP3+ nTregs or CD3+CD4−CD8− double negative T cells and systemic immune activation.
Design: A prospective longitudinal study of patients with early PHI.
Methods: Twenty-five patients were included. Relationships between frequency of Treg subsets and T-cell activation, assessed on fresh peripheral blood mononuclear cells, were analyzed using nonparametric tests. Cytokine production by double negative T cells was assessed following anti-CD3/anti-CD28 stimulation.
Results: No relationship was found between T-cell activation and frequencies of nTregs. In contrast, a strong negative relationship was found at baseline between the proportion of double negative T cells and the proportion of activated CD8 T cells coexpressing CD38 and HLA-DR (P = 0.005) or expressing Ki-67 (P = 0.002). In addition, the frequency of double negative T cells at baseline negatively correlated with the frequency of HLA-DR+CD38+CD8+ T cells at month 6, defining the immune activation set point (P = 0.031). High proportions of stimulated double negative T cells were found to produce the immunosuppressive cytokines transforming growth factor-β1 and/or IL-10.
Conclusion: The proportion of double negative T cells at baseline was found to be predictive of the immune activation set point. Our data strongly suggest that double negative T cells may control immune activation in PHI. This effect might be mediated through the production of TGF-β1/IL-10 known to downmodulate immune activation.

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Available from: Gael Petitjean, Feb 05, 2014
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    • "In addition, supported by the findings of the current study, endogenous, monocyte/macrophage-targeted, antiinflammatory mechanisms are also likely to contribute to ongoing immunosuppression with TGF-í µí»½1 appearing to play a pivotal role. Notwithstanding platelets, plasmacytoid dendritic cells, macrophages of the M2 phenotype, and immunoregulatory CD8 + T cells, immunosuppressive and profibrotic TGF-í µí»½1 is likely to originate predominantly from regulatory T cells [38] [39]. In this context it is noteworthy that extensive fibrosis of the T-cell zone of lymphoid tissue appears to be a significant factor in the failure of T-cell reconstitution following successful HAART [13]. "
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    ABSTRACT: Few studies have examined immune activation profiles in patients with advanced HIV-1 subtype C infection or assessed their potential to predict responsiveness to HAART. BioPlex, ELISA, and nephelometric procedures were used to measure plasma levels of inflammatory biomarkers in HIV-1 subtype C-infected patients sampled before and after 6 months of successful HAART (n = 20); in patients failing HAART (n = 30); and in uninfected controls (n = 8). Prior to HAART, CXCL9, CXCL10, β 2M, sTNF-R1, TGF- β 1, IFN- γ , IL-6, TNF, and sCD14 were significantly elevated in HIV-1-infected patients compared to controls (P < 0.01). All of these markers, with the exception of sTNF-R1, were also elevated in patients failing HAART (P < 0.05). The persistently elevated levels of CXCL9, CXCL10, and β 2M in patients failing therapy in the setting of a marked reduction in these markers in patients on successful HAART suggest that they may be useful not only to monitor immune activation during HAART, but also to distinguish between good and poor responders. In the case of sCD14 and TGF- β 1, the levels of these biomarkers remained persistently elevated despite HAART-induced virological suppression, a finding that is consistent with ongoing monocyte-macrophage activation, underscoring a potential role for adjuvant anti-inflammatory therapy.
    Mediators of Inflammation 04/2014; 2014:198413. DOI:10.1155/2014/198413 · 3.24 Impact Factor
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    • "Secondly, the increase in the immunosuppressive cytokine, IL-10, we observed in the Ido1−/− caput extracts may also participate in the new immune equilibrium. Although Treg is the major provider of IL-10, it has been shown that several other cell types can also produce it; including Th1, Th2, cytotoxic T cells, B lymphocytes, mast cells, mononuclear phagocytes, APCs as well as TDN cells [34], [55]. More investigations will be necessary to identify which cell(s) type(s) in the caput epididymis of Ido1−/− animals is responsible for the increased production of IL-10. "
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    ABSTRACT: The epididymis maintains a state of immune tolerance towards spermatozoa while also protecting them and itself against infection and acute inflammation. The immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (Ido1) participates in this delicate local equilibrium. Using the mouse Ido1(-/-) model, we show here that the absence of IDO1 expression leads in the epididymis but not in serum to (1) an increase in the inflammatory state as evidenced by changes in the content of cytokines and chemokines, (2) the engagement of a Th1-driven inflammatory response as evidenced by changes in the Th17/Treg as well as Th1/Th2 equilibria, as well as (3) differences in the content of lipid intermediates classically involved in inflammation. Despite this more pronounced inflammatory state, Ido1(-/-) animals succeed in preserving the local epididymal immune situation due to the activation of compensatory mechanisms that are discussed.
    PLoS ONE 06/2013; 8(6):e66494. DOI:10.1371/journal.pone.0066494 · 3.23 Impact Factor
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    ABSTRACT: This review summarizes the role of CD3+CD4-CD8- double-negative T cells, which have both regulatory and helper T-cell functions and may have the potential to compensate for the reduced levels of CD4 T cells during SIV/HIV infection. Double-negative T cells have been characterized in several human diseases and in murine models of autoimmunity and transplantation, where they exhibit both immunoregulatory and helper T-cell-like function. During the natural nonpathogenic SIV infection of African nonhuman primates, the lack of clinical disease progression is associated with the presence of double-negative T cells that maintain helper T-cell functions while remaining refractory to viral infection. Moreover, DN T cells may compensate for very low levels of CD4+ T cells observed in a cohort of SIV-infected sooty mangabeys that have remained free of clinical AIDS for over 10 years. These studies identify a potential for double-negative T cells to provide critical helper function during HIV infection. Double-negative T cells with some CD4+ T-cell functions are associated with a nonpathogenic outcome during SIV infection and represent a potential immune therapeutic target in HIV-infected patients.
    Current opinion in HIV and AIDS 03/2012; 7(2):164-71. DOI:10.1097/COH.0b013e3283504a66 · 4.68 Impact Factor
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