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 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 D(b)NP(366)(+)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.