Dynamics and genomic landscape of CD8+ T cells undergoing hepatic priming

Alexandre P. Bénéchet, Giorgia De Simone, Pietro Di Lucia, Francesco Cilenti, Giulia Barbiera, Nina Le Bert, Valeria Fumagalli, Eleonora Lusito, Federica Moalli, Valentina Bianchessi, Francesco Andreata, Paola Zordan, Elisa Bono, Leonardo Giustini, Weldy V. Bonilla, Camille Bleriot, Kamini Kunasegaran, Gloria Gonzalez-Aseguinolaza, Daniel D. Pinschewer, Patrick T.F. KennedyLuigi Naldini, Mirela Kuka, Florent Ginhoux, Alessio Cantore, Antonio Bertoletti, Renato Ostuni, Luca G. Guidotti, Matteo Iannacone

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Abstract

The responses of CD8+ T cells to hepatotropic viruses such as hepatitis B range from dysfunction to differentiation into effector cells, but the mechanisms that underlie these distinct outcomes remain poorly understood. Here we show that priming by Kupffer cells, which are not natural targets of hepatitis B, leads to differentiation of CD8+ T cells into effector cells that form dense, extravascular clusters of immotile cells scattered throughout the liver. By contrast, priming by hepatocytes, which are natural targets of hepatitis B, leads to local activation and proliferation of CD8+ T cells but not to differentiation into effector cells; these cells form loose, intravascular clusters of motile cells that coalesce around portal tracts. Transcriptomic and chromatin accessibility analyses reveal unique features of these dysfunctional CD8+ T cells, with limited overlap with those of exhausted or tolerant T cells; accordingly, CD8+ T cells primed by hepatocytes cannot be rescued by treatment with anti-PD-L1, but instead respond to IL-2. These findings suggest immunotherapeutic strategies against chronic hepatitis B infection.

Original languageEnglish
Pages (from-to)200-205
Number of pages6
JournalNature
Volume574
Issue number7777
DOIs
Publication statusPublished - Oct 10 2019

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Cite this

Bénéchet, A. P., De Simone, G., Di Lucia, P., Cilenti, F., Barbiera, G., Le Bert, N., Fumagalli, V., Lusito, E., Moalli, F., Bianchessi, V., Andreata, F., Zordan, P., Bono, E., Giustini, L., Bonilla, W. V., Bleriot, C., Kunasegaran, K., Gonzalez-Aseguinolaza, G., Pinschewer, D. D., ... Iannacone, M. (2019). Dynamics and genomic landscape of CD8+ T cells undergoing hepatic priming. Nature, 574(7777), 200-205. https://doi.org/10.1038/s41586-019-1620-6