title: Induction of cytokine production in naive CD4(+) T cells by antigen-presenting murine liver sinusoidal endothelial cells but failure to induce differentiation toward Th1 cells.
abstract: OBJECTIVE
  Murine liver sinusoidal endothelial cells (LSECs) constitutively express accessory molecules and can present antigen to memory Th1 CD4(+) T cells. Using a T-cell receptor transgenic mouse line, we addressed the question whether LSECs can prime naive CD4(+) T cells.
  
  
  METHODS
  Purified LSECs were investigated for their ability to induce activation and differentiation of naive CD4(+) T cells in comparison with bone marrow-derived antigen-presenting cells and macrovascular endothelial cells. Activation of T cells was determined by cytokine production. LSECs were further studied for expression of interleukin (IL)-12 by reverse-transcription polymerase chain reaction, and the unique phenotype of LSECs was determined by flow cytometry.
  
  
  RESULTS
  We provide evidence that antigen-presenting LSECs can activate naive CD62Lhigh CD4(+) T cells. Activation of naive CD4(+) T cells by LSECs occurred in the absence of IL-12. In contrast, macrovascular endothelial cells from aorta could not activate naive CD4(+) T cells. The unique functional characteristics of microvascular LSECs together with a unique phenotype (CD4(+), CD11b+, CD11c+, CD80(+), CD86(+)) make these cells different from macrovascular endothelial cells. Furthermore, LSECs did not require in vitro maturation to activate naive CD4(+) T cells. Most importantly, LSECs failed to induce differentiation toward Th1 cells, whereas conventional antigen-presenting cell populations induced a Th1 phenotype in activated CD4(+) T cells. Upon restimulation, CD4(+) T cells, which were primed by antigen-presenting LSECs, expressed interferon gamma, IL-4, and IL-10, which is consistent with a Th0 phenotype. Exogenous cytokines (IL-1beta, IL-12, or IL-18) present during T-cell priming by antigen-presenting LSECs could not induce a Th1 phenotype, but neutralization of endogenously produced IL-4 during T-cell priming led to a reduced expression of IL-4 and IL-10 by CD4(+) T cells upon restimulation. The addition of spleen cells to cocultures of LSECs and naive CD4(+) T cells during T-cell priming led to differentiation of T cells toward a Th1 phenotype.
  
  
  CONCLUSIONS
  The ability of antigen-presenting LSECs to induce cytokine expression in naive CD4(+) T cells and their failure to induce differentiation toward a Th1 phenotype may contribute to the unique hepatic microenvironment that is known to promote tolerance.
authors.affiliation: Zentrum für Molekulare Biologie, Ruprecht-Karls-Universität Heidelberg, Germany. P.Knolle@ZMBH.Uni-Heidelberg
authors.forename: P A
authors.initials: PA
authors.lastname: Knolle
authors.forename: E
authors.initials: E
authors.lastname: Schmitt
authors.forename: S
authors.initials: S
authors.lastname: Jin
authors.forename: T
authors.initials: T
authors.lastname: Germann
authors.forename: R
authors.initials: R
authors.lastname: Duchmann
authors.forename: S
authors.initials: S
authors.lastname: Hegenbarth
authors.forename: G
authors.initials: G
authors.lastname: Gerken
authors.forename: A W
authors.initials: AW
authors.lastname: Lohse
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000502:physiology*; D015415:Biomarkers; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D004727:Endothelium / Q000166:cytology; D005260:Female; D015870:Gene Expression / Q000502:physiology; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000235:genetics / Q000494:pharmacology; D008099:Liver / Q000166:cytology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000166:cytology; D010641:Phenotype; D018417:Th1 Cells / Q000502:physiology*
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018664:Interleukin-12; D007371:Interferon-gamma