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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2089-2100.e8
JournalImmunity
Volume54
Issue number9
DOIs
Publication statusPublished - Sep 14 2021

Keywords

  • CD8 T cells
  • hepatitis B virus
  • imaging
  • interleukin-2
  • Kupffer cells
  • liver
  • scRNA-seq
  • single cell
  • T cell dysfunction
  • tolerance

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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