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Inversion of the Vδ1 to Vδ2 γδ T cell ratio in CVID is not restored by IVIg and is associated with immune activation and exhaustion.

ABSTRACT: Common variable immunodeficiency (CVID) is defined by low levels of IgG and IgA, but perturbations in T cells are also commonly found. However, there is limited information on γδ T cells in CVID patients. Newly diagnosed CVID patients (n = 15) were enrolled before and after intravenous IgG (IVIg) replacement therapy. Cryopreserved peripheral blood mononuclear cells were then used to study γδ T cells and CVID patients were compared to healthy controls (n = 22). The frequency and absolute count of Vδ1 γδ T cells was found to be increased in CVID (median 0.60% vs 2.64%, P <0.01 and 7.5 vs 39, P <0.01 respectively), while they were decreased for Vδ2 γδ T cells (median, 2.36% vs 0.74%, P <0.01 and 37.8 vs 13.9, P <0.01 respectively) resulting in an inversion of the Vδ1 to Vδ2 ratio (0.24 vs 1.4, P <0.001). Markers of immune activation were elevated on all subsets of γδ T cells, and HLA-DR expression was associated with an expansion of Vδ1 γδ T cells (r = 0.73, P = 0.003). Elevated PD-1 expression was found only on Vδ2 γδ T cells (median 1.15% vs 3.08%, P <0.001) and was associated with the decrease of Vδ2 γδ T cells (r = -0.67, P = 0.007). IVIg had no effect on the frequency of Vδ1 and Vδ2 γδ T cells or HLA-DR expression, but alleviated CD38 expression on Vδ1 γδ T cells (median MFI 965 vs 736, P <0.05). These findings suggest that immunological perturbations of γδ T cells are a general feature associated with CVID and are only partially reversed by IVIg therapy.

SUBMITTER: Paquin-Proulx D

PROVIDER: S-EPMC5265843 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Inversion of the Vδ1 to Vδ2 γδ T cell ratio in CVID is not restored by IVIg and is associated with immune activation and exhaustion.

Paquin-Proulx Dominic D Barsotti Nathália Silveira NS Santos Bianca A N BAN Marinho Ana Karolina B B AKBB Kokron Cristina M CM Carvalho Karina I KI Barros Myrthes T MT Kalil Jorge J Nixon Douglas F DF Kallas Esper G EG

Medicine 20160701 30

Common variable immunodeficiency (CVID) is defined by low levels of IgG and IgA, but perturbations in T cells are also commonly found. However, there is limited information on γδ T cells in CVID patients. Newly diagnosed CVID patients (n = 15) were enrolled before and after intravenous IgG (IVIg) replacement therapy. Cryopreserved peripheral blood mononuclear cells were then used to study γδ T cells and CVID patients were compared to healthy controls (n = 22). The frequency and absolute count of ...[more]

PMID: 27472706

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Project description:BackgroundWe previously reported that Vδ2+Vγ9+ γδ T cells were significantly decreased in multiple sclerosis (MS) patients without disease-modifying therapies (untreated MS) and were negatively correlated with Expanded Disability Status Scale (EDSS) scores, suggesting protective roles of Vδ2+Vγ9+ γδ T cells. Interferon-β (IFN-β) is one of the first-line disease-modifying drugs for MS. However, no previous studies have reported changes in γδ T cell subsets under IFN-β treatment. Therefore, we aimed to clarify the effects of the long-term usage of IFN-β on γδ T cell subsets in MS patients.MethodsComprehensive flow cytometric immunophenotyping was performed in 35 untreated MS and 21 MS patients on IFN-β for more than 2 years (IFN-β-treated MS) including eight super-responders fulfilling no evidence of disease activity criteria, and 44 healthy controls (HCs).ResultsThe percentages of Vδ2+Vγ9+ cells in γδ T cells were significantly lower in untreated and IFN-β-treated MS patients than in HCs. By contrast, the percentages of Vδ1-Vδ2-Vγ9- cells in γδ T cells were markedly higher in IFN-β-treated MS patients than in HCs and untreated MS patients (both p < 0.001). A significant negative correlation between the percentages of Vδ2+Vγ9+ cells in γδ T cells and EDSS scores was confirmed in untreated MS but not evident in IFN-β-treated MS. Moreover, class-switched memory B cells were decreased in IFN-β-treated MS compared with HCs (p < 0.001) and untreated MS patients (p = 0.006). Interestingly, the percentages of Vδ1-Vδ2-Vγ9- cells in γδ T cells were negatively correlated with class-switched memory B cell percentages in all MS patients (r = - 0.369, p = 0.005), and the percentages of Vδ1-Vδ2-Vγ9- cells in Vδ1-Vδ2- γδ T cells were negatively correlated with EDSS scores only in IFN-β super-responders (r = - 0.976, p < 0.001).ConclusionsThe present study suggests that long-term usage of IFN-β increases Vδ1-Vδ2-Vγ9- γδ T cells, which are associated with a better outcome, especially in IFN-β super-responders. Thus, increased Vδ1-Vδ2-Vγ9- cells together with decreased class-switched memory B cells may contribute to the suppression of disease activity in MS patients under IFN-β treatment.

Project description:Although conventional regulatory T cells (Tregs) are sufficient in controlling low residual T-cell activation in ART-treated patients, they are not efficient in controlling exaggerated immune activation associated with high levels of HIV replication in primary HIV infection (PHI). Our previous data suggested that double negative (DN) T cells including mainly γδ DN T cells play a role in the control of immune activation in PHI. Since γδ T cells are capable of exerting regulatory functions, we investigated their implication as Tregs in PHI as well as chronic HIV infection (CHI). In a cross-sectional study of 58 HIV-infected patients, in the primary and the chronic phase either ART-treated or untreated (UT), we analyzed phenotype and cytokine production of γδ T cells using flow cytometry. Cytokine production was assessed following in vitro stimulation with isopentenyl pyrophosphate or plate-bound anti-CD3/anti-CD28 monoclonal antibodies. We found that the proportion of γδ T cells negatively correlated with CD8 T-cell activation in PHI patients. Furthermore, we found that in these patients, the Vδ2 receptor bearing (Vδ2+) γδ T cells were strongly activated, exhibited low terminal differentiation, and produced the anti-inflammatory cytokine, TGF-β. In contrast, in UT-CHI, we observed a remarkable expansion of γδ T cells, where the Vδ2+ γδ T cells comprised of an elevated proportion of terminally differentiated cells producing high levels of IFN-γ but very low levels of TGF-β. We also found that this loss of regulatory feature of γδ T cells in CHI was a lasting impairment as we did not find recovery of TGF-β production even in ART-CHI patients successfully treated for more than 5 years. Our data therefore suggest that during the primary HIV infection, Vδ2+ γδ T cells may act as Tregs controlling immune activation through production of TGF-β. However, in CHI, γδ T cells transform from an anti-inflammatory into pro-inflammatory cytokine profile and participate in sustenance of immune activation.

Dataset Information

Inversion of the Vδ1 to Vδ2 γδ T cell ratio in CVID is not restored by IVIg and is associated with immune activation and exhaustion.

Publications

Inversion of the Vδ1 to Vδ2 γδ T cell ratio in CVID is not restored by IVIg and is associated with immune activation and exhaustion.

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