High expression of CD38 and MHC class II on CD8+ T cells during severe influenza disease reflects bystander activation and trogocytosis
AuthorJia, X; Chua, B; Loh, L; Koutsakos, M; Kedzierski, L; Olshanski, M; Heath, W; Xu, J; Wang, Z; Kedzierska, K
University of Melbourne Author/sKedzierski, Lukasz; Chua, Brendon; Heath, William; Kedzierska, Katherine; Wang, Zhongfang; Koutsakos, Marios
AffiliationMicrobiology and Immunology
Veterinary and Agricultural Sciences
Document TypeJournal Article
CitationsJia, X., Chua, B., Loh, L., Koutsakos, M., Kedzierski, L., Olshanski, M., Heath, W., Xu, J., Wang, Z. & Kedzierska, K. (2021). High expression of CD38 and MHC class II on CD8+ T cells during severe influenza disease reflects bystander activation and trogocytosis. pp.2021.02.09.430410-. https://doi.org/10.1101/2021.02.09.430410.
Access StatusOpen Access
Although co-expression of CD38 and HLA-DR on CD8 + T cells reflects activation during influenza, SARS-CoV-2, Dengue, Ebola and HIV-1 viral infections, high and prolonged CD38 + HLA-DR + expression can be associated with severe and fatal disease outcomes. As the expression of CD38 + HLA-DR + is poorly understood, we used mouse models of influenza A/H7N9, A/H3N2 and A/H1N1 infection to investigate the mechanisms underpinning CD38 + MHC-II + phenotype on CD8 + T-cells. Our 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 the respiratory tract during severe infection. To understand the mechanisms underlying CD38 and MHC-II expression, we also used adoptively-transferred transgenic OT-I CD8 + T-cells recognising the ovalbumin-derived K b SIINFEKL epitope and A/H1N1-SIINKEKL infection. Strikingly, we found that OT-I cells adoptively-transferred into MHC-II −/− mice did not display MHC-II after influenza virus infection, suggesting that MHC-II was acquired via trogocytosis in wild-type mice. Additionally, detection of CD19 on CD38 + MHC II + OT-I cells further supports that MHC-II was acquired by trogocytosis, at least partially, sourced from B-cells. Our results also revealed that co-expression of CD38 + MHC II + on CD8 + T-cells was needed for the optimal recall ability following secondary viral challenge. Overall, our study provides evidence 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 expression occurs via trogocytosis from antigen-presenting cells. Our findings also highlight the importance of the CD38 + MHC II + phenotype for CD8 + T-cell memory establishment and recall. <h4>Summary</h4> Co-expression of CD38 and MHC-II on CD8 + T cells is recognized as a classical hallmark of activation during viral infections. High and prolonged CD38 + HLA-DR + expression, however, can be associated with severe disease outcomes and the mechanisms are unclear. Using our established influenza wild-type and transgenic mouse models, we determined how disease severity affected the activation of influenza-specific CD38 + MHC-II + CD8 + T cell responses in vivo and the antigenic determinants that drive their activation and expansion. Overall, our study provides evidence 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 expression occurs, at least in part, via trogocytosis from antigen-presenting cells. Our findings also highlight the importance of the CD38 + MHC II + phenotype for CD8 + T-cell memory establishment and recall.
- Click on "Export Reference in RIS Format" and choose "open with... Endnote".
- Click on "Export Reference in RIS Format". Login to Refworks, go to References => Import References