Fine phenotypic and functional characterization of effector cluster of differentiation 8 positive T cells in human patients with primary biliary cirrhosis
✍ Scribed by Masanobu Tsuda; Yoko M. Ambrosini; Weici Zhang; Guo-Xiang Yang; Yugo Ando; Guanghua Rong; Koichi Tsuneyama; Kosuke Sumida; Shinji Shimoda; Christopher L. Bowlus; Patrick S.C. Leung; Xiao-Song He; Ross L. Coppel; Aftab A. Ansari; Zhe-Xiong Lian; M. Eric Gershwin
- Publisher
- John Wiley and Sons
- Year
- 2011
- Tongue
- English
- Weight
- 440 KB
- Volume
- 54
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
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 1 and CD8 1 T-cell responses. Recent data from murine models have suggested that liver-infiltrating CD8 1 cells play a critical role in biliary destruction in PBC. We hypothesized that chronic antigen stimulation of CD8 1 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 1 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 high CD57 1 CD8 high , but expressing the gut homing integrin, a4b7, 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 high CD57 1 CD8 high T cells express higher levels of granzyme A, granzyme B, perforin, CCR5 and a4b7, and lower levels of CCR7 and CD28 than other CD8 high T cells. Furthermore, interleukin (IL)-5 produced by CD8 1 CD57 1 T lymphocytes upon in vitro T-cell receptor stimulation are increased in PBC. Histologically, CD8 1 CD57 1 T cells accumulate around the portal area in PBC. Moreover, CD8 1 CD57 1 T cells respond specifically to the major histocompatibility class I epitope of PDC-E2. Conclusion: In conclusion, our data demonstrate that CD45RO high CD57 1 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. (HEPATOLOGY 2011;54:1293-1302) P rimary biliary cirrhosis (PBC) is a female-predominant, organ-specific autoimmune disease characterized by destruction of intrahepatic small bile duct biliary epithelial cells (BECs). 1 The serologi-cal hallmark of PBC is the presence of antimitochondrial autoantibodies (AMAs) directed against the pyruvate dehydrogenase E2 complex (PDC-E2) located in the inner membrane of mitochondria.