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

Jia, Xiaoxiao; Chua, Brendon Y; Loh, Liyen; Koutsakos, Marios; Kedzierski, Lukasz; Olshansky, Moshe; Heath, William R; Chang, So Young; Xu, Jianqing; Wang, Zhongfang; Kedzierska, Katherine

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.