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

Objectives: Although co-expression of CD38 and HLA-DR reflects T-cell activation during viral infections, high and prolonged CD38HLA-DR expression is associated with severe disease. To date, the mechanism underpinning expression of CD38HLA-DR is poorly understood.

Methods: We used mouse models of influenza A/H9N2, A/H7N9 and A/H3N2 infection to investigate mechanisms underpinning CD38MHC-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 DNP CD8 T-cell responses showed that CD38MHC-II co-expression was detected on both virus-specific and bystander CD8 T cells, with increased numbers of both CD38MHC-IICD8 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 CD38MHC-II OT-I cells supports the proposition that MHC-II was acquired by trogocytosis sourced from B cells. Co-expression of CD38MHC-II on CD8 T cells was needed for optimal recall following secondary infection.

Conclusions: Overall, our study demonstrates that both virus-specific and bystander CD38MHC-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 CD38MHC-II phenotype for CD8 T-cell recall.