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

Abstract 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 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 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 KbSIINFEKL 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.Summary 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 responsesin vivoand 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..

Medienart:	Preprint

Erscheinungsjahr:	2023
Erschienen:	2023

Enthalten in:	bioRxiv.org - (2023) vom: 20. Okt. Zur Gesamtaufnahme - year:2023

Sprache:	Englisch

Beteiligte Personen:	Jia, Xiaoxiao [VerfasserIn] Chua, Brendon Y [VerfasserIn] Loh, Liyen [VerfasserIn] Koutsakos, Marios [VerfasserIn] Kedzierski, Lukasz [VerfasserIn] Olshanski, Moshe [VerfasserIn] Heath, William R [VerfasserIn] Xu, Jianqing [VerfasserIn] Wang, Zhongfang [VerfasserIn] Kedzierska, Katherine [VerfasserIn]

Links:	Volltext [lizenzpflichtig] Volltext [kostenfrei]

Themen:	570 Biology

doi:	10.1101/2021.02.09.430410

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PPN (Katalog-ID):	XBI019913036