title: Liver sinusoidal endothelial cell-mediated CD8 T cell priming depends on co-inhibitory signal integration over time.
abstract: The initiation of adaptive immunity requires cell-to-cell contact between T cells and antigen-presenting cells. Together with immediate TCR signal transduction, the formation of an immune synapse (IS) is one of the earliest events detected during T cell activation. Here, we show that interaction of liver sinusoidal endothelial cells (LSEC) with naive CD8 T cells, which induces CD8 T cells without immediate effector function, is characterized by a multi-focal type IS. The co-inhibitory molecule B7H1, which is pivotal for the development of non-responsive LSEC-primed T cells, did not alter IS structure or TCRβ/CD11a cluster size or density, indicating that IS form does not determine the outcome of LSEC-mediated T cell activation. Instead, PD-1 signaling during CD8 T cell priming by LSEC repressed IL-2 production as well as sustained CD25 expression. When acting during the first 24 h of LSEC/CD8 T cell interaction, CD28 co-stimulation inhibited the induction of non-responsive LSEC-primed T cells. However, after more than 36 h of PD-1 signaling, CD28 co-stimulation failed to rescue effector function in LSEC-primed T cells. Together, these data show that during LSEC-mediated T cell priming, integration of co-inhibitory PD-1 signaling over time turns on a program for CD8 T cell development, that cannot be overturned by co-stimulatory signals.
authors.affiliation: Institute of Molecular Medicine at the LIMES Institute, University of Bonn, Bonn, Germany.
authors.forename: Julita
authors.initials: J
authors.lastname: Kaczmarek
authors.affiliation: Department of Membrane Biochemistry at the LIMES Institute, University of Bonn, Bonn, Germany.
authors.forename: Yahya
authors.initials: Y
authors.lastname: Homsi
authors.affiliation: Department of Membrane Biochemistry at the LIMES Institute, University of Bonn, Bonn, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: van Üüm
authors.affiliation: Institute of Molecular Medicine at the LIMES Institute, University of Bonn, Bonn, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Metzger
authors.affiliation: Institute of Molecular Immunology, Technical University Munich, Munich, Germany.
authors.forename: Percy A
authors.initials: PA
authors.lastname: Knolle
authors.affiliation: Department of Molecular Immunology at the LIMES Institute, University of Bonn, Bonn, Germany.
authors.forename: Waldemar
authors.initials: W
authors.lastname: Kolanus
authors.affiliation: Department of Membrane Biochemistry at the LIMES Institute, University of Bonn, Bonn, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Lang
authors.affiliation: Institute of Molecular Medicine at the LIMES Institute, University of Bonn, Bonn, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Diehl
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D040881:CD11a Antigen / Q000378:metabolism; D018106:CD28 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002450:Cell Communication; D002452:Cell Count; D048429:Cell Size; D045142:Cross-Priming / Q000276:immunology*; D042783:Endothelial Cells / Q000378:metabolism*; D054992:Immunological Synapses / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis; D008099:Liver / Q000166:cytology*; D008810:Mice, Inbred C57BL; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013997:Time Factors
chemical_list: D040881:CD11a Antigen; D018106:CD28 Antigens; D007376:Interleukin-2; D016693:Receptors, Antigen, T-Cell, alpha-beta