Biochemistry and Pharmacology - Research Publications
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ItemHigh expression of CD38 and MHC class II on CD8+ T cells during severe influenza disease reflects bystander activation and trogocytosis(WILEY, 2021)OBJECTIVES: Although co-expression of CD38 and HLA-DR reflects T-cell activation during viral infections, high and prolonged CD38+HLA-DR+ expression is associated with severe disease. To date, the mechanism underpinning expression of CD38+HLA-DR+ is poorly understood. METHODS: We used mouse models of influenza A/H9N2, A/H7N9 and A/H3N2 infection to investigate mechanisms underpinning CD38+MHC-II+ phenotype on CD8+ T cells. To further understand MHC-II trogocytosis on murine CD8+ T cells as well as the significance behind the scenario, we used adoptively transferred transgenic OT-I CD8+ T cells and A/H3N2-SIINKEKL infection. RESULTS: Analysis of influenza-specific immunodominant DbNP366 +CD8+ T-cell responses showed that CD38+MHC-II+ co-expression was detected on both virus-specific and bystander CD8+ T cells, with increased numbers of both CD38+MHC-II+CD8+ T-cell populations observed in immune organs including the site of infection during severe viral challenge. OT-I cells adoptively transferred into MHC-II-/- mice had no MHC-II after infection, suggesting that MHC-II was acquired via trogocytosis. The detection of CD19 on CD38+MHC-II+ OT-I cells supports the proposition that MHC-II was acquired by trogocytosis sourced from B cells. Co-expression of CD38+MHC-II+ on CD8+ T cells was needed for optimal recall following secondary infection. CONCLUSIONS: Overall, our study demonstrates that both virus-specific and bystander CD38+MHC-II+ CD8+ T cells are recruited to the site of infection during severe disease, and that MHC-II presence occurs via trogocytosis from antigen-presenting cells. Our findings highlight the importance of the CD38+MHC-II+ phenotype for CD8+ T-cell recall.
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ItemMetabolic characteristics of CD8+ T cell subsets in young and aged individuals are not predictive of functionality (vol 11, 2857, 2020)(NATURE PUBLISHING GROUP, 2020-07-09)An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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ItemMetabolic characteristics of CD8+ T cell subsets in young and aged individuals are not predictive of functionality(NATURE PUBLISHING GROUP, 2020-06-05)Virtual memory T (TVM) cells are antigen-naïve CD8+ T cells that exist in a semi-differentiated state and exhibit marked proliferative dysfunction in advanced age. High spare respiratory capacity (SRC) has been proposed as a defining metabolic characteristic of antigen-experienced memory T (TMEM) cells, facilitating rapid functionality and survival. Given the semi-differentiated state of TVM cells and their altered functionality with age, here we investigate TVM cell metabolism and its association with longevity and functionality. Elevated SRC is a feature of TVM, but not TMEM, cells and it increases with age in both subsets. The elevated SRC observed in aged mouse TVM cells and human CD8+ T cells from older individuals is associated with a heightened sensitivity to IL-15. We conclude that elevated SRC is a feature of TVM, but not TMEM, cells, is driven by physiological levels of IL-15, and is not indicative of enhanced functionality in CD8+ T cells.