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. 2015 Apr 20;10(4):e0124659.
doi: 10.1371/journal.pone.0124659. eCollection 2015.

Attrition of TCR Vα7.2+ CD161++ MAIT cells in HIV-tuberculosis co-infection is associated with elevated levels of PD-1 expression

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Attrition of TCR Vα7.2+ CD161++ MAIT cells in HIV-tuberculosis co-infection is associated with elevated levels of PD-1 expression

Alireza Saeidi et al. PLoS One. .

Abstract

Mucosal-associated invariant T (MAIT) cells are evolutionarily conserved antimicrobial MR1-restricted CD8(+) T cells co-expressing the semi-invariant TCR Vα7.2, and are numerous in the blood and mucosal tissues of humans. MAIT cells appear to undergo exhaustion in chronic viral infections. However, their role in human immunodeficiency virus type 1 (HIV-1) mono-infection and HIV/tuberculosis (TB) co-infection have seldom been elaborately investigated. We conducted a cross-sectional study to investigate the frequencies and phenotypes of CD161(++)CD8(+) T cells among anti-retroviral therapy (ART)/anti-TB therapy (ATT) treatment-naïve HIV/TB co-infected, ART/TB treated HIV/TB co-infected, ART naïve HIV-infected, ART-treated HIV-infected patients, and HIV negative healthy controls (HCs) by flow cytometry. Our data revealed that the frequency of MAIT cells was severely depleted in HIV mono- and HIV/TB co-infections. Further, PD-1 expression on MAIT cells was significantly increased in HIV mono- and HIV-TB co-infected patients. The frequency of MAIT cells did not show any significant increase despite the initiation of ART and/or ATT. Majority of the MAIT cells in HCs showed a significant increase in CCR6 expression as compared to HIV/TB co-infections. No marked difference was seen with expressions of chemokine co-receptor CCR5 and CD103 among the study groups. Decrease of CCR6 expression appears to explain why HIV-infected patients display weakened mucosal immune responses.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Phenotypic properties of CD161++CD8+ T-cells.
(A) Depiction of the gating strategy used: During acquisition, lymphocytes were selected on the basis of forward-scatter and side-scatter characteristics. MAIT cell subsets were gated from CD3, CD8 and CD161bright cells, viz., CD3+CD8+CD161++ defined as MAIT cells. (B) Histograms (gated on the CD8+ T-cell population) show differential expression of TCR Vα7.2 by CD161++, CD161+ and CD161-CD8+ T cells from a representative sample from healthy controls (HC). (C) Collective data from 10 HCs demonstrated differential expression of PD-1 by CD161++, CD161+ and CD161-CD8+ T cells. (D) Aggregate data from 10 HCs demonstrated differential expression of CCR6 by CD161++, CD161+ and CD161- CD8+ T-cell subsets. All graphs show median (red bars) and range (blue whiskers); P values are reported for two-sided Mann-Whitney tests with threshold for significance P = 0.02 after Bonferroni correction for 2 comparisons.
Fig 2
Fig 2. Percentage of CD8+ T cells expressing CD161++ across different study groups.
(A) Scatter plots (gated on the CD3+ T-cell population) show co-staining with CD8 and CD161 on representative samples from 5 different clinical groups: CPTNs, CPTPs, HVTNs, HVTPs, and HCs. (B) CD161++CD8+ T (MAIT cell) frequency in HCs showed significantly increased MAIT cell levels compared to other study groups. (C) CD161+CD8+ T cell frequency showed no difference across the different study groups. (D-E) CD161++CD8+ MAIT cell frequency in subjects with HIV mono-infection and HIV/TB co-infection shows no significant correlation with either HIV plasma viral load (copies/mL) or CD4+ T-cell counts (cells/mm3). All graphs show median (red bars) and range (blue whiskers); P values are reported for two-sided Mann-Whitney tests with threshold for significance P = 0.025 after Bonferroni correction for 2 comparisons. Correlations between MAIT cell frequency and markers of HIV disease progression were assessed using two-tailed non-parametric Spearman’s rank. (Note: TN, treatment naïve; TP, treatment positive; HC, healthy control; CP, HIV/TB co-infection; HV, HIV mono-infection).
Fig 3
Fig 3. Expression levels of different markers by CD161++CD8+ T-cell subsets in the study population.
(A) Zebra plots of double-gating strategy (gated on the CD161++ CD8+ T cells) show staining with 4 different markers (CD103, PD-1, CCR6, CCR5) on representative samples from a HC and a CPTN. HCs showed increased amount of CCR6-expressing MAIT cells and decreased amount of PD-1 expressing MAIT cells compared to CPTNs. (B) HC showed significantly lower expression level of inhibitory receptor, PD-1 while HIV/TB co-infected patients show significantly increased PD-1 expressing MAIT cells. (C) Significantly increased CCR6-expressing MAIT cells were found in HCs compared to HIV and TB infected groups. (D) No significant difference was observed in CCR5 expression levels by MAIT cells among the different study subjects. The significant difference in CCR5 expression between HVTPs and HCs may be due to the limited number of samples. All graphs show median (red bars) and range (blue whiskers); P values are reported for two-sided Mann-Whitney tests with threshold for significance P = 0.025 after Bonferroni correction for 2 comparisons. (Note: TN, treatment naïve; TP, treatment positive; HC, healthy control; CP, HIV/TB co-infection; HV, HIV mono-infection).
Fig 4
Fig 4. Profile of expression of CD161 on MAIT cells.
(A) The zebra plots depict the gating strategy for the analysis of expression of CD161 on MAIT cells. CD8+ T cells were gated for TCR Vα7.2 specific for MAIT cells. After gating on CD8+ TCR Vα7.2+ MAIT cell population, CD161 expression was subsequently analyzed. (B-C) MAIT cells of HCs showed significant increase of CD161 compared to other infected groups. Conversely, HCs has the lowest amount of CD161- MAIT cells. All graphs show median (red bars) and range (blue whiskers); P values are reported for two-sided Mann-Whitney tests with threshold for significance P = 0.025 after Bonferroni correction for 2 comparisons. (Note: TN, treatment naïve; TP, treatment positive; HC, healthy control; CP, HIV/TB co-infection; HV, HIV mono-infection).
Fig 5
Fig 5. Correlation analysis between PD-1 expression and CD161++/MAIT cell frequency in the study participants.
The MAIT cells frequency correlated inversely with PD-1 expression on MAIT cells (P = 0.0039 and r = -0.4006). Correlation analysis between CD161++/MAIT cell frequencies and PD-1 expression was performed using the Spearman's rank correlation coefficient.

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