Autoimmune, Cholestatic and Biliary Disease
Article first published online: 27 SEP 2011
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 54, Issue 4, pages 1293–1302, October 2011
How to Cite
Tsuda, M., Ambrosini, Y. M., Zhang, W., Yang, G.-X., Ando, Y., Rong, G., Tsuneyama, K., Sumida, K., Shimoda, S., Bowlus, C. L., Leung, P. S.C., He, X.-S., Coppel, R. L., Ansari, A. A., Lian, Z.-X. and Eric Gershwin, M. (2011), Fine phenotypic and functional characterization of effector cluster of differentiation 8 positive T cells in human patients with primary biliary cirrhosis. Hepatology, 54: 1293–1302. doi: 10.1002/hep.24526
Potential conflict of interest: Nothing to report.
Financial support for this work was provided by the National Institutes of Health (grant DK39588; Bethesda, MD).
- Issue published online: 27 SEP 2011
- Article first published online: 27 SEP 2011
- Accepted manuscript online: 6 JUL 2011 12:46PM EST
- Manuscript Accepted: 18 JUN 2011
- Manuscript Received: 31 JAN 2011
In primary biliary cirrhosis (PBC), patients develop a multilineage response to a highly restricted peptide of the E2 component of pyruvate dehydrogenase (PDC-E2) involving autoantibody and autoreactive cluster of differentiation (CD)4+ and CD8+ T-cell responses. Recent data from murine models have suggested that liver-infiltrating CD8+ cells play a critical role in biliary destruction in PBC. We hypothesized that chronic antigen stimulation of CD8+ T cells alters effector memory T cell (TEM) frequency and function similar to that seen with chronic viral infections, including failure to terminally differentiate and relative resistance to apoptosis. We have rigorously phenotyped CD8+ T-cell subpopulations from 132 subjects, including 76 patients with PBC and 56 controls, and report a higher frequency of TEM cells characterized as CD45ROhighCD57+CD8high, but expressing the gut homing integrin, α4β7, in peripheral blood mononuclear cells of PBC. These CD8high TEM cells have reduced expression of Annexin V after TCR stimulation. Consistent with a TEM phenotype, CD45ROhighCD57+CD8high T cells express higher levels of granzyme A, granzyme B, perforin, CCR5 and α4β7, and lower levels of CCR7 and CD28 than other CD8high T cells. Furthermore, interleukin (IL)-5 produced by CD8+CD57+ T lymphocytes upon in vitro T-cell receptor stimulation are increased in PBC. Histologically, CD8+CD57+ T cells accumulate around the portal area in PBC. Moreover, CD8+CD57+ T cells respond specifically to the major histocompatibility class I epitope of PDC-E2. Conclusion: In conclusion, our data demonstrate that CD45ROhighCD57+CD8high T cells are a subset of terminally differentiated cytotoxic TEM cells, which could play a critical role in the progressive destruction of biliary epithelial cells. (HEPATOLOGY 2011;54:1293–1302)