title: Liver sinusoidal endothelial cell cross-priming is supported by CD4 T cell-derived IL-2.
abstract: Liver sinusoidal endothelial cells (LSECs) are prominent liver-resident antigen (cross-)presenting cells. LSEC cross-priming of naïve CD8 T cells does not require CD4 T cell help in contrast to priming by dendritic cells (DC) but leads to the formation of memory T cells that is preceded by transient Granzyme B (GzmB) expression. Here we provide evidence for a so far unrecognized CD4 T helper cell function in LSEC-induced CD8 T cell activation.
  
  
  
  Naïve CD8 T cells and differentiated T helper 1 (Th1) cells were stimulated by antigen-presenting LSEC, and GzmB expression in CD8 T cells was determined by flow cytometry. To identify molecular pathways mediating this GzmB expression, mechanistic proof-of-concept experiments were conducted using stimulatory anti-CD3 antibody together with Hyper-IL-6.
  
  
  
  We demonstrate that LSECs simultaneously function in antigen co-presentation to CD8 and CD4 T cells. Such co-presentation revealed a function of Th1 cells to increase GzmB expression in CD8 T cells after LSEC but not DC cross-priming. IL-2 released from Th1 cells was required but not sufficient for rapid GzmB induction in CD8 T cells. T cell receptor together with IL-6 trans-signaling was necessary for IL-2 to mediate rapid GzmB induction.
  
  
  
  Our findings indicate that LSECs can serve as a platform to facilitate CD4-CD8 T cell crosstalk enhancing the immune function of LSECs to cross-prime CD8 T cells. IL-6 trans-signaling-mediated responsiveness for IL-2 inducing sustained GzmB expression in CD8 T cells reveals unique mechanisms of CD4 T cell help and CD8 T cell differentiation through liver-resident antigen-presenting cells.
  
  
  
  Our findings demonstrate that LSEC co-present antigen to CD8 and CD4 T cells and thereby enable CD4 T cell help for LSEC-priming of CD8 T cells. This CD4 T cell help selectively enhances the rapid upregulation of GzmB and effector function of LSEC-primed CD8 T cells thereby enhancing functional differentiation towards CD8 effector T cells.
authors.affiliation: Institute of Experimental Immunology, University Hospital Bonn, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Wittlich
authors.affiliation: Institute of Molecular Immunology and Experimental Oncology, Klinikum München rechts der Isar, Technische Universität München, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Dudek
authors.affiliation: Institute of Experimental Immunology, University Hospital Bonn, Germany.
authors.forename: Jan P
authors.initials: JP
authors.lastname: Böttcher
authors.affiliation: Institute of Experimental Immunology, University Hospital Bonn, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Schanz
authors.affiliation: Institute of Molecular Immunology and Experimental Oncology, Klinikum München rechts der Isar, Technische Universität München, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Hegenbarth
authors.affiliation: Institute of Immunology, University Hospital Mainz, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bopp
authors.affiliation: Institute of Immunology, University Hospital Mainz, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Schmitt
authors.affiliation: Institute of Experimental Immunology, University Hospital Bonn, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kurts
authors.affiliation: Institute of Biochemistry, Kiel University, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Garbers
authors.affiliation: Institute of Biochemistry, Kiel University, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose John
authors.affiliation: Institute of Experimental Immunology, University Hospital Bonn, Germany; Institute of Molecular Immunology and Experimental Oncology, Klinikum München rechts der Isar, Technische Universität München, Germany.
authors.forename: Percy A
authors.initials: PA
authors.lastname: Knolle
authors.affiliation: Institute of Molecular Immunology and Experimental Oncology, Klinikum München rechts der Isar, Technische Universität München, Germany. Electronic address: dirk.wohlleber@tum.de.
authors.forename: Dirk
authors.initials: D
authors.lastname: Wohlleber
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002450:Cell Communication; D002478:Cells, Cultured; D045142:Cross-Priming; D042783:Endothelial Cells / Q000276:immunology*; D053804:Granzymes / Q000032:analysis; D007376:Interleukin-2 / Q000502:physiology*; D008099:Liver / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D007376:Interleukin-2; D053804:Granzymes
keywords: CD4 T cell help; IL-6 trans-signaling; LSEC; Liver primed T cells