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. 2022 Apr 4;207(2):141-148.
doi: 10.1093/cei/uxab004.

Mucosal-associated invariant T cells are activated in an interleukin-18-dependent manner in Epstein-Barr virus-associated T/natural killer cell lymphoproliferative diseases

Yuriko Ishikawa  1 , Masaki Yamada  1 , Naomi Wada  1 , Etsuko Takahashi  1 , Ken-Ichi Imadome  1
Affiliations

Mucosal-associated invariant T cells are activated in an interleukin-18-dependent manner in Epstein-Barr virus-associated T/natural killer cell lymphoproliferative diseases

Yuriko Ishikawa et al. Clin Exp Immunol. .

Abstract

Mucosal-associated invariant T (MAIT) cells are a type of innate immune cells that protect against some infections. However, the involvement of MAIT cells in Epstein-Barr virus-associated T/natural killer cell lymphoproliferative diseases (EBV-T/NK-LPD) is unclear. In this study, we found that MAIT cells were highly activated in the blood of patients with EBV-T/NK-LPD. MAIT cell activation levels correlated with disease severity and plasma IL-18 levels. Stimulation of healthy peripheral blood mononuclear cells with EBV resulted in activation of MAIT cells, and this activation level was enhanced by exogenous IL-18. MAIT cells stimulated by IL-18 might thus be involved in the immunopathogenesis of EBV-T/NK-LPD.

Keywords: Epstein-Barr virus; interleukin-18; mucosal-associated innate T cell.

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Figures

Fig. 1
Fig. 1
Mucosal-associated invariant T (MAIT) cells are activated in the blood of patients with Epstein–Barr virus-associated T/natural killer cell lymphoproliferative diseases (EBV-T/NK-LPD). (A) Representative dot plots of healthy controls (HC) and patients with chronic active Epstein–Barr virus infection (CAEBV). Cells enclosed within the square are the MAIT (CD3+CD8+Vα7.2+CD161++) cells. (B) Frequency of MAIT (CD3+CD8+Vα7.2+CD161++) cells in CD3+CD8+ T cells in the blood of HC (n = 11) and patients with CAEBV (n = 22) and EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) (n = 7). (C) Activation levels of MAIT cells in the blood of healthy controls (n = 11) and patients with EBV-T/NK-LPD (n = 23). (D) Correlation between the frequency and activation levels of MAIT cells in the blood of patients with EBV-T/NK-LPD (n = 23). Statistical significance was determined using (B) one-way ANOVA with Tukey’s correction, (C) the Mann–Whitney U test, and (D) Spearman’s rank correlation matrix.
Fig. 2
Fig. 2
Mucosal-associated invariant T (MAIT) cell activation level is associated with disease severity of Epstein–Barr virus-associated T/natural killer cell lymphoproliferative diseases (EBV-T/NK-LPD). (A) Correlation between serum alanine aminotransferase (ALT) (n = 21), aspartate amino transferase (AST) (n = 21), lactate dehydrogenase (LDH) (n = 21), ferritin (n = 21), soluble IL-2 receptor (sIL-2R) (n = 19) levels, and activation levels of MAIT cells in the blood of patients with EBV-T/NK-LPD. (B) Relationship between MAIT cell activation levels and presence (+) or absence (−) of hepatosplenomegaly in EBV-T/NK-LPD (n = 21). Statistical significance was determined using (A) Spearman’s rank correlation matrix and (B) the Mann–Whitney U test.
Fig. 3
Fig. 3
Correlation between plasma IL-18 levels and activation levels of mucosal-associated invariant T (MAIT) cells in the blood of patients with Epstein–Barr virus-associated T/natural killer cell lymphoproliferative diseases (EBV-T/NK-LPD) (n = 21). Statistical significance was determined using Spearman’s rank correlation matrix.
Fig. 4
Fig. 4
Mucosal-associated invariant T (MAIT) cells are activated in the presence of Epstein–Barr virus (EBV); IL-18 synergistically enhances this response. (A) Peripheral blood mononuclear cells (PBMCs; 1.0 × 106) from healthy donor 1 were cultured in triplicate in the presence of combinations of 1.0 × 106 copies of EBV, IL-18 (1, 10, or 100 ng/ml), IL-18 neutralizing antibody (2.5 µg/ml), and isotype control antibody (2.5 µg/ml) for 24 h. The granzyme B and IFN-γ expression in MAIT cells was then analyzed using flow cytometry. (B) PBMCs (1.0 × 106) from healthy donor 1 were stimulated with 1.0 × 106 copies of EBV in RPMI 1640 supplemented with 10% fetal bovine serum. Cell culture medium was used as the mock control. After 24 h, culture supernatants were harvested, and concentrations of IL-18 and other cytokines were measured using enzyme-linked immunosorbent assay and multiplex cytokine assay, respectively. Statistical significance was determined using (A) one-way ANOVA with Tukey’s correction (†) and two-way ANOVA with Tukey’s correction (‡), and (B) a paired t-test.
Fig. 5
Fig. 5
Myeloid cells produce IL-18 in the presence of Epstein–Barr virus (EBV). CD14+, CD3+, CD19+, and CD56+ cells were isolated from peripheral blood mononuclear cells (PBMCs) of healthy donor 1. The cells were cultured in triplicate for 24 h with or without 1.0 × 106 copies of EBV, and IL-18 concentration in the culture supernatants was measured using enzyme-linked immunosorbent assay. Cell culture medium was used as the mock control. Statistical significance was determined using a paired t-test.
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