High expression of CD38 and MHC class II on CD8+ T cells during severe influenza disease reflects bystander activation and trogocytosis.

Abstract

ObjectivesAlthough 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.MethodsWe 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.ResultsAnalysis 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.ConclusionsOverall, 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.