Fine phenotypic and functional characterization of effector cluster of differentiation 8 positive T cells in human patients with primary biliary cirrhosis

Masanobu Tsuda, Yoko M. Ambrosini, Weici Zhang, Guo Xiang Yang, Yugo Ando, Guanghua Rong, Koichi Tsuneyama, Kosuke Sumida, Shinji Shimoda, Christopher Bowlus, Patrick S Leung, Xiaosong He, Ross L. Coppel, Aftab A. Ansari, Zhe Xiong Lian, M. Eric Gershwin

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39 Scopus citations

Abstract

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 (T EM) 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 T EM cells characterized as CD45RO highCD57 +CD8 high, but expressing the gut homing integrin, α4β7, in peripheral blood mononuclear cells of PBC. These CD8 high T EM cells have reduced expression of Annexin V after TCR stimulation. Consistent with a T EM phenotype, CD45RO highCD57 +CD8 high T cells express higher levels of granzyme A, granzyme B, perforin, CCR5 and α4β7, and lower levels of CCR7 and CD28 than other CD8 high 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 CD45RO highCD57 +CD8 high T cells are a subset of terminally differentiated cytotoxic T EM cells, which could play a critical role in the progressive destruction of biliary epithelial cells.

Original languageEnglish (US)
Pages (from-to)1293-1302
Number of pages10
JournalHepatology
Volume54
Issue number4
DOIs
StatePublished - Oct 2011

ASJC Scopus subject areas

  • Hepatology

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    Tsuda, M., Ambrosini, Y. M., Zhang, W., Yang, G. X., Ando, Y., Rong, G., Tsuneyama, K., Sumida, K., Shimoda, S., Bowlus, C., Leung, P. S., He, X., Coppel, R. L., Ansari, A. A., Lian, Z. X., & Gershwin, M. E. (2011). Fine phenotypic and functional characterization of effector cluster of differentiation 8 positive T cells in human patients with primary biliary cirrhosis. Hepatology, 54(4), 1293-1302. https://doi.org/10.1002/hep.24526