Identification of a Kupffer cell subset capable of reverting the T cell dysfunction induced by hepatocellular priming

Immunity. 2021 Sep 14;54(9):2089-2100.e8. doi: 10.1016/j.immuni.2021.05.005.

Giorgia De Simone ¹, Francesco Andreata ², Camille Bleriot ³, Valeria Fumagalli ¹, Chiara Laura ⁴, José M Garcia-Manteiga ⁵, Pietro Di Lucia ², Stefano Gilotto ⁶, Xenia Ficht ², Federico F De Ponti ², Elisa B Bono ², Leonardo Giustini ², Gioia Ambrosi ², Marta Mainetti ², Paola Zordan ², Alexandre P Bénéchet ², Micol Ravà ², Svetoslav Chakarov ³, Federica Moalli ², Marc Bajenoff ⁷, Luca G Guidotti ¹, Florent Ginhoux ⁸, Matteo Iannacone ⁹

Affiliations

1 Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Vita-Salute San Raffaele University, 20132 Milan, Italy.
2 Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
3 Singapore Immunology Network (SIgN), Agency for Science, Technology & Research (A(∗)STAR), 8A Biomedical Grove, Immunos Building #3-4, Biopolis, Singapore 138648.
4 Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Vita-Salute San Raffaele University, 20132 Milan, Italy; Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
5 Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
6 Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
7 Aix Marseille University, CNRS, INSERM, CIML, Marseille 13288, France.
8 Singapore Immunology Network (SIgN), Agency for Science, Technology & Research (A(∗)STAR), 8A Biomedical Grove, Immunos Building #3-4, Biopolis, Singapore 138648; Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China; Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, 169856, Singapore.
9 Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Vita-Salute San Raffaele University, 20132 Milan, Italy; Experimental Imaging Centre, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. Electronic address: [email protected].

PMID: 34469774 DOI: 10.1016/j.immuni.2021.05.005

Abstract

Kupffer cells (KCs) are highly abundant, intravascular, liver-resident macrophages known for their scavenger and phagocytic functions. KCs can also present antigens to CD8⁺ T cells and promote either tolerance or effector differentiation, but the mechanisms underlying these discrepant outcomes are poorly understood. Here, we used a mouse model of hepatitis B virus (HBV) Infection, in which HBV-specific naive CD8⁺ T cells recognizing hepatocellular antigens are driven into a state of immune dysfunction, to identify a subset of KCs (referred to as KC2) that cross-presents hepatocellular antigens upon interleukin-2 (IL-2) administration, thus improving the Antiviral function of T cells. Removing MHC-I from all KCs, including KC2, or selectively depleting KC2 impaired the capacity of IL-2 to revert the T cell dysfunction induced by intrahepatic priming. In summary, by sensing IL-2 and cross-presenting hepatocellular antigens, KC2 overcome the tolerogenic potential of the hepatic microenvironment, suggesting new strategies for boosting hepatic T cell immunity.

Keywords

CD8(+) T cells; Kupffer cells; T cell dysfunction; hepatitis B virus; imaging; interleukin-2; liver; scRNA-seq; single cell; tolerance.

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