Liver sinusoidal endothelial cell-mediated CD8 T cell priming depends on co-inhibitory signal integration over time

TY - JOUR

T1 - Liver sinusoidal endothelial cell-mediated CD8 T cell priming depends on co-inhibitory signal integration over time

AU - Kaczmarek, Julita

AU - Homsi, Yahya

AU - van Üüm, Jan

AU - Metzger, Christina

AU - Knolle, Percy A

AU - Kolanus, Waldemar

AU - Lang, Thorsten

AU - Diehl, Linda

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - Animals

KW - Antigen-Presenting Cells

KW - Antigens, CD11a

KW - Antigens, CD28

KW - CD8-Positive T-Lymphocytes

KW - Cell Communication

KW - Cell Count

KW - Cell Size

KW - Cross-Priming

KW - Endothelial Cells

KW - Immunological Synapses

KW - Interleukin-2

KW - Liver

KW - Mice, Inbred C57BL

KW - Receptors, Antigen, T-Cell, alpha-beta

KW - Signal Transduction

KW - Time Factors

U2 - 10.1371/journal.pone.0099574

DO - 10.1371/journal.pone.0099574

M3 - SCORING: Journal article

C2 - 24924593

VL - 9

SP - e99574

JO - PLOS ONE

JF - PLOS ONE

SN - 1932-6203

IS - 6

ER -