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

Alexandre P. Bénéchet, Giorgia Simone, Pietro Lucia, Francesco Cilenti, Giulia Barbiera, Nina 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. Kennedy, Luigi Naldini, Mirela Kuka, Florent Ginhoux, Alessio Cantore, Antonio Bertoletti, Renato Ostuni, Luca G. Guidotti and Matteo Iannacone ()
Additional contact information
Alexandre P. Bénéchet: Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute
Giorgia Simone: Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute
Pietro Lucia: Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute
Francesco Cilenti: Vita-Salute San Raffaele University
Giulia Barbiera: IRCCS San Raffaele Scientific Institute
Nina Bert: Duke-NUS Medical School
Valeria Fumagalli: Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute
Eleonora Lusito: IRCCS San Raffaele Scientific Institute
Federica Moalli: Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute
Valentina Bianchessi: Vita-Salute San Raffaele University
Francesco Andreata: Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute
Paola Zordan: Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute
Elisa Bono: Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute
Leonardo Giustini: Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute
Weldy V. Bonilla: University of Basel
Camille Bleriot: Technology & Research (A∗STAR)
Kamini Kunasegaran: Duke-NUS Medical School
Gloria Gonzalez-Aseguinolaza: Centre for Applied Medical Research
Daniel D. Pinschewer: University of Basel
Patrick T. F. Kennedy: Queen Mary University of London
Luigi Naldini: Vita-Salute San Raffaele University
Mirela Kuka: Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute
Florent Ginhoux: Technology & Research (A∗STAR)
Alessio Cantore: Vita-Salute San Raffaele University
Antonio Bertoletti: Duke-NUS Medical School
Renato Ostuni: Vita-Salute San Raffaele University
Luca G. Guidotti: Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute
Matteo Iannacone: Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute

Nature, 2019, vol. 574, issue 7777, 200-205

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1620-6

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