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.