Article first published online: 24 JUN 2011
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 54, Issue 1, pages 262–272, July 2011
How to Cite
Schildberg, F. A., Wojtalla, A., Siegmund, S. V., Endl, E., Diehl, L., Abdullah, Z., Kurts, C. and Knolle, P. A. (2011), Murine hepatic stellate cells veto CD8 T cell activation by a CD54-dependent mechanism. Hepatology, 54: 262–272. doi: 10.1002/hep.24352
Potential conflict of interest: Nothing to report.
This work was supported by the German Research Foundation (through grant SFB704 to Percy A. Knolle and Christian Kurts and through grant SFBTR57 to Percy A. Knolle, Christian Kurts, and Sören V. Siegmund), the Helmholtz Alliance (through a grant to Percy A. Knolle), the Virtual Liver Network (through a grant to Percy A. Knolle), the German National Academic Foundation (through a Ph.D. fellowship to Frank A. Schildberg), and BONFOR (through an institutional grant to Frank A. Schildberg).
- Issue published online: 24 JUN 2011
- Article first published online: 24 JUN 2011
- Accepted manuscript online: 12 APR 2011 08:17AM EST
- Manuscript Revised: 31 MAR 2011
- Manuscript Received: 27 OCT 2010
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. (HEPATOLOGY 2011;)