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. 2018 Aug;109(8):2383-2390.
doi: 10.1111/cas.13654. Epub 2018 Jun 27.

Human T-cell lymphotropic/leukemia virus type 1 (HTLV-1) Tax-specific T-cell exhaustion in HTLV-1-infected individuals

Ayako Masaki  1   2 , Takashi Ishida  1   3 , Susumu Suzuki  4 , Asahi Ito  1 , Tomoko Narita  1 , Shiori Kinoshita  1 , Masaki Ri  1 , Shigeru Kusumoto  1 , Hirokazu Komatsu  1 , Hiroshi Inagaki  2 , Ryuzo Ueda  4 , Shinsuke Iida  1
Affiliations

Human T-cell lymphotropic/leukemia virus type 1 (HTLV-1) Tax-specific T-cell exhaustion in HTLV-1-infected individuals

Ayako Masaki et al. Cancer Sci. 2018 Aug.

Abstract

Adult T-cell leukemia/lymphoma (ATL) is caused by Human T-cell lymphotropic/leukemia virus type 1 (HTLV-1), and a higher HTLV-1 provirus load in PBMC is a risk factor for ATL development. Here, we document a significant inverse correlation between the function of HTLV-1 Tax-specific CTL (Tax-CTL), as assessed by ex vivo cytokine production in response to cognate peptide, and the HTLV-1 provirus load in PBMC in both HTLV-1 asymptomatic carriers (AC) (Spearman rank correlation coefficient [Rs] = -0.494, P = .037, n = 18) and ATL patients (Rs = -0.774, P = .001, n = 15). There was also a significant correlation between the HTLV-1 provirus load and the percentage of PD-1-positive Tax-CTL in both HTLV-1 AC (Rs = 0.574, P = .013) and ATL patients (Rs = 0.676, P = .006). Furthermore, the percentage of PD-1-positive Tax-CTL was inversely correlated with their function in HTLV-1 AC (Rs = -0.542, P = .020), and ATL patients (Rs = -0.639, P = .010). These findings indicate that the function of Tax-CTL decreased as their programmed cell death protein 1 (PD-1) levels increased, parallel to the increased HTLV-1 provirus load in PBMC. We propose that functional Tax-CTL are crucial for determining the HTLV-1 provirus load in PBMC, not only in HTLV-1 AC, but also in ATL, and that PD-1 expression levels are reliable markers of Tax-CTL function. Thus, modulating the immunological equilibrium between Tax-CTL and HTLV-1-infected cells to achieve dominance of functional effectors could represent an ideal strategy for controlling HTLV-1-associated disease.

Keywords: CTL; HTLV-1; Tax; adult T-cell leukemia/lymphoma; programmed cell death protein 1.

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Figures

Figure 1
Figure 1
Relationships between programmed cell death protein 1 (PD‐1) positivity of Human T‐cell lymphotropic/leukemia virus type 1 (HTLV‐1) Tax‐specific cytotoxic T cells (Tax‐CTL) and the production of interferon (IFN)‐γ and tumor necrosis factor (TNF)‐α ex vivo in response to cognate peptide in HTLV‐1 asymptomatic carriers (AC). A, Correlation between HTLV‐1 provirus load in PBMC and the percentage of PD‐1‐positive Tax‐CTL in HTLV‐1 AC. There was a significant positive correlation between these two factors (Rs = 0.574, P = .013). B, Correlation between the percentage of PD‐1‐positive Tax‐CTL and the percentage of both IFN‐γ‐ and TNF‐α‐producing Tax‐CTL ex vivo in response to cognate peptide. There was a significant inverse correlation between these 2 factors (Rs = −0.542, P = .020). C, Correlation between the HTLV‐1 provirus load in PBMC and the percentage of both IFN‐γ‐ and TNF‐α‐producing Tax‐CTL ex vivo in response to cognate peptide. There was a significant inverse correlation between these 2 factors (Rs = −0.494, P = .037). D, Lymphocyte populations from HTLV‐1 AC donors 1, 2, 3, and 4 showing CD8 and HTLV‐1 Tax tetramer positivity. CD8 and HTLV‐1 Tax tetramer‐positive cells are gated as shown by the red squares (left panels), and plotted to show T‐cell immunoglobulin and mucin domain‐containing protein‐3 (TIM‐3) and PD‐1 positivity. Percentages of PD‐1‐positive but TIM‐3‐negative, and of PD‐1‐ and TIM‐3‐double‐positive cells are indicated in each panel (second left). CD8 and HTLV‐1 Tax tetramer‐positive cells are plotted to show lymphocyte‐activation gene 3 (LAG‐3) and cytotoxic T‐lymphocyte‐associated antigen 4 (CTLA‐4) positivity. Percentage of LAG‐3‐positive but CTLA‐4‐negative cells is indicated (second right). PBMC obtained from HTLV‐1 AC 1, 2, 3, and 4 were cocultured with or without cognate peptide (final concentration 100 nmol/L) at 37°C in 5% CO 2 for 3 h, after which brefeldin A was added. The cells were then incubated for an additional 2 h. Subsequently, IFN‐γ and TNF‐α production from Tax‐CTL was evaluated. Percentage of Tax‐CTL producing both IFN‐γ and TNF‐α in response to cognate peptide is indicated in each panel (right‐hand side). Plots labeled 1, 2, 3, and 4 in (A,B,C), correspond to 1, 2, 3, and 4, in (D), respectively. Plots labeled 2, 3, and 4 in (A,B,C) are colored blue, green, and brown, respectively
Figure 2
Figure 2
Relationships between programmed cell death protein 1 (PD‐1) positivity of Human T‐cell lymphotropic/leukemia virus type 1 (HTLV‐1) Tax‐specific cytotoxic T cells (Tax‐CTL) and their production of interferon (IFN)‐γ and tumor necrosis factor (TNF)‐α ex vivo in response to cognate peptide in adult T‐cell leukemia/lymphoma (ATL) patients. A, Correlation between HTLV‐1 provirus load in PBMC and the percentage of PD‐1‐positive Tax‐CTL in ATL patients. There was a significant positive correlation between these 2 factors (Rs = 0.676, P = .006). B, Correlation between the percentage of PD‐1‐positive Tax‐CTL and the percentage of Tax‐CTL producing both IFN‐γ and TNF‐α ex vivo in response to the cognate peptide. There was a significant inverse correlation between these 2 factors (Rs = −0.639, P = .010). C, Correlation between HTLV‐1 provirus load in PBMC and the percentage of Tax‐CTL producing both IFN‐γ and TNF‐α ex vivo in response to cognate peptide. There was a significant inverse correlation between these 2 factors (Rs = −0.774, P = .001). The 4 symbols in gray in the plots (A,B,C) indicate ATL patients after allogeneic hematopoietic stem cell transplantation (HSCT). D, Lymphocyte populations of PBMC, ex vivo, from ATL patients 1, 2, 3, and 4 are plotted to show CD8 and HTLV‐1 Tax tetramer positivity. CD8 and HTLV‐1 Tax tetramer‐positive cells are shown gated by the red squares (left panels), and are plotted to show T‐cell immunoglobulin and mucin domain‐containing protein‐3 (TIM‐3) and PD‐1 positivity. Percentages of PD‐1‐positive but TIM‐3‐negative, and of PD‐1‐, TIM‐3‐double‐positive cells are indicated in each panel (second left). CD8 and HTLV‐1 Tax tetramer‐positive cells are plotted to show lymphocyte‐activation gene 3 (LAG‐3) and cytotoxic T‐lymphocyte‐associated antigen 4 (CTLA‐4) positivity. Percentage of LAG‐3‐positive but CTLA‐4‐negative cells is indicated second right. PBMC obtained from ATL patients 1, 2, 3, and 4 were cocultured with or without cognate peptide (final concentration 100 nmol/L) at 37°C in 5% CO 2 for 3 h, after which brefeldin A was added. The cells were then incubated for an additional 2 h. Subsequently, IFN‐γ and TNF‐α production from Tax‐CTL was evaluated. Percentage of both IFN‐γ‐ and TNF‐α‐producing Tax‐CTL in response to cognate peptide is indicated in each panel (right panels). Plots labeled 1, 2, 3, and 4 in (A,B,C) correspond to 1, 2, 3, and 4, in (D), respectively. Plots labeled 2, 3, and 4 in (A,B,C) are colored blue, green, and brown, respectively
Figure 3
Figure 3
Relationships between the absolute number of Tax‐specific cytotoxic T cells (Tax‐CTL) and the Human T‐cell lymphotropic/leukemia virus type 1 (HTLV‐1) provirus load in PBMC from HTLV‐1 asymptomatic carriers (AC) and in adult T‐cell leukemia/lymphoma (ATL) patients. A, No significant correlation between HTLV‐1 provirus load in PBMC and the absolute number of PD‐1‐negative Tax‐CTL in HTLV‐1 AC (Rs = −0.152, P = .548). B, No significant correlation between HTLV‐1 provirus load in PBMC and the absolute number of PD‐1‐positive Tax‐CTL in HTLV‐1 AC (Rs = 0.126, P = .618). C, Significant inverse correlation between HTLV‐1 provirus load in PBMC and the absolute number of PD‐1‐negative Tax‐CTL in ATL patients (Rs = −0.561, P = .029). D, No significant correlation between HTLV‐1 provirus load in PBMC and the absolute number of PD‐1‐positive Tax‐CTL in ATL patients (Rs = −0.061, P = .830). Plots labeled 1, 2, 3, and 4 in (A,B) correspond to 1, 2, 3, and 4 in Figure 1, respectively. Plots labeled 1, 2, 3, and 4 in (C,D) correspond to 1, 2, 3, and 4 in Figure 2, respectively. The 4 symbols in gray in (C,D) indicate ATL patients after allogeneic hematopoietic stem cell transplantation
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