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Murine hepatic stellate cells veto CD8 T cell activation by a CD54-dependent mechanism

Created: 18th Jul 2012 at 17:12
Last updated: 24th Oct 2013 at 16:18

Abstract:

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.