Murine hepatic stellate cells veto CD8 T cell activation by a CD54-dependent mechanism
Standard
Murine hepatic stellate cells veto CD8 T cell activation by a CD54-dependent mechanism. / Schildberg, Frank A; Wojtalla, Alexandra; Siegmund, Sören V; Endl, Elmar; Diehl, Linda; Abdullah, Zeinab; Kurts, Christian; Knolle, Percy A.
In: HEPATOLOGY, Vol. 54, No. 1, 07.2011, p. 262-72.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Murine hepatic stellate cells veto CD8 T cell activation by a CD54-dependent mechanism
AU - Schildberg, Frank A
AU - Wojtalla, Alexandra
AU - Siegmund, Sören V
AU - Endl, Elmar
AU - Diehl, Linda
AU - Abdullah, Zeinab
AU - Kurts, Christian
AU - Knolle, Percy A
N1 - Copyright © 2011 American Association for the Study of Liver Diseases.
PY - 2011/7
Y1 - 2011/7
N2 - UNLABELLED: The liver has a role in T cell tolerance induction, which is mainly achieved through the functions of tolerogenic hepatic antigen-presenting cells (APCs) and regulatory T cells. Hepatic stellate cells (HSCs) are known to have various immune functions, which range from immunogenic antigen presentation to the induction of T cell apoptosis. Here we report a novel role for stellate cells in vetoing the priming of naive CD8 T cells. Murine and human HSCs and stromal cells (but not hepatocytes) prevented the activation of naive T cells by dendritic cells, artificial APCs, and phorbol 12-myristate 13-acetate/ionomycin by a cell contact-dependent mechanism. The veto function for inhibiting T cell activation was directly correlated with the activation state of HSCs and was most pronounced in HSCs from fibrotic livers. Mechanistically, high expression levels of CD54 simultaneously restricted the expression of interleukin-2 (IL-2) receptor and IL-2 in T cells, and this was responsible for the inhibitory effect because exogenous IL-2 overcame the HSC veto function.CONCLUSION: Our results demonstrate a novel function of HSCs in the local skewing of immune responses in the liver through the prevention of local stimulation of naive T cells. These results not only indicate a beneficial role in hepatic fibrosis, for which increased CD54 expression on HSCs could attenuate further T cell activation, but also identify IL-2 as a key cytokine in mediating local T cell immunity to overcome hepatic tolerance.
AB - UNLABELLED: The liver has a role in T cell tolerance induction, which is mainly achieved through the functions of tolerogenic hepatic antigen-presenting cells (APCs) and regulatory T cells. Hepatic stellate cells (HSCs) are known to have various immune functions, which range from immunogenic antigen presentation to the induction of T cell apoptosis. Here we report a novel role for stellate cells in vetoing the priming of naive CD8 T cells. Murine and human HSCs and stromal cells (but not hepatocytes) prevented the activation of naive T cells by dendritic cells, artificial APCs, and phorbol 12-myristate 13-acetate/ionomycin by a cell contact-dependent mechanism. The veto function for inhibiting T cell activation was directly correlated with the activation state of HSCs and was most pronounced in HSCs from fibrotic livers. Mechanistically, high expression levels of CD54 simultaneously restricted the expression of interleukin-2 (IL-2) receptor and IL-2 in T cells, and this was responsible for the inhibitory effect because exogenous IL-2 overcame the HSC veto function.CONCLUSION: Our results demonstrate a novel function of HSCs in the local skewing of immune responses in the liver through the prevention of local stimulation of naive T cells. These results not only indicate a beneficial role in hepatic fibrosis, for which increased CD54 expression on HSCs could attenuate further T cell activation, but also identify IL-2 as a key cytokine in mediating local T cell immunity to overcome hepatic tolerance.
KW - Animals
KW - Antigen-Presenting Cells
KW - Apoptosis
KW - CD8-Positive T-Lymphocytes
KW - Cell Communication
KW - Cell Line
KW - Cells, Cultured
KW - Dendritic Cells
KW - Disease Models, Animal
KW - Hepatic Stellate Cells
KW - Humans
KW - Intercellular Adhesion Molecule-1
KW - Interleukin-2
KW - Liver Cirrhosis
KW - Mice
KW - Mice, Inbred BALB C
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Models, Animal
KW - T-Lymphocytes, Regulatory
U2 - 10.1002/hep.24352
DO - 10.1002/hep.24352
M3 - SCORING: Journal article
C2 - 21488077
VL - 54
SP - 262
EP - 272
JO - HEPATOLOGY
JF - HEPATOLOGY
SN - 0270-9139
IS - 1
ER -