Vδ2 T cell subsets, defined by PD-1 and TIM-3 expression, present varied cytokine responses in acute myeloid leukemia patients

• Published in: International immunopharmacology Vol. 80; p. 106122
• Main Authors: Wu, Kangni, Feng, Juan, Xiu, Yanghui, Li, Zhifeng, Lin, Zhijuan, Zhao, Haijun, Zeng, Hanyan, Xia, Weilin, Yu, Lian, Xu, Bing
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2020; Elsevier BV
• Subjects: Acute myeloid leukemia; Adult; Antibodies; Blocking antibodies; Cytokines; Female; Hepatitis A Virus Cellular Receptor 2 - immunology; Humans; Impact prediction; Inflammation; Interferon-gamma - genetics; Interferon-gamma - immunology; Interleukin 2; Intraepithelial Lymphocytes - immunology; Leukemia; Leukemia, Myeloid, Acute - immunology; Lymphocytes; Lymphocytes T; Male; Middle Aged; Myeloid leukemia; PD-1; PD-1 protein; PD-L1 protein; Programmed Cell Death 1 Receptor - immunology; Stem cell transplantation; Stem cells; TIM-3; Transplantation; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - immunology; Tumor necrosis factor-α; Vδ2 T cell; γ-Interferon; Vδ2 T cell; TIM-3; PD-1; Acute myeloid leukemia
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2019.106122

•The levels of PD-1+TIM-3+ Vδ2 T cells were significantly higher in AML patients.•PD-1+TIM-3− subset presented the highest TNF-α and IFN-γ expression.•PD-1+TIM-3+ subset presented the lowest TNF-α and IFN-γ expression.•Anti-TIM-3 inhibition and anti-PD-1/TIM-3 dual inhibition elevated TNF-α and IFN-γ.•Anti-PD-1 blocking antibodies increased the frequency of TIM-3+ cells in Vδ2 T cells. Vδ2 T cells represent the major γδ T cell subset in humans and can serve as an important early source of TNF-α and IFN-γ during inflammatory responses. In acute myeloid leukemia (AML) patients receiving allogeneic stem cell transplantation, higher γδ T cell count predicted better prognosis. The impact of PD-1 and TIM-3 expression on the function of Vδ2 T cells is yet unclear. In this study, we showed that the frequencies of PD-1+TIM-3− Vδ2 T cells were comparable between healthy controls and AML patients, but the frequencies of PD-1−TIM-3+ Vδ2 T cells and of PD-1+TIM-3+ Vδ2 T cells were significantly higher in AML patients than in healthy controls. Both PD-1 and TIM-3 were upregulated upon phosphoantigen + IL-2 activation, but the relative differences in the frequencies of various PD-1 vs. TIM-3 subsets between AML patients and healthy controls remained. Interestingly, among all PD-1 vs. TIM-3 subsets, the PD-1+TIM-3− subset presented the highest TNF-α and IFN-γ expression, while the PD-1+TIM-3+ subset presented the lowest TNF-α and IFN-γ expression. Anti-PD-1 inhibition did not significantly affect the production of TNF-α or IFN-γ, but anti-TIM-3 inhibition and anti-PD-1/TIM-3 dual inhibition significantly elevated the production of TNF-α and IFN-γ. Interestingly, anti-PD-1 blocking antibodies had significantly increased the frequency of TIM-3+ cells in Vδ2 T cells, suggesting a compensatory TIM-3 upregulation. In addition, the levels of PD-L1 and HMGB-1 were significantly higher in AML patients than in healthy subjects. In summary, this study provides knowledge on the cytokine expression patterns by PD-1 and/or TIM-3-expressing Vδ2 T cells in AML patients, and indicates that the upregulation of PD-1 alone is insufficient to indicate functional impairment, and Vδ2 T cells may require anti-TIM-3 inhibition for functional revival.