title: Fine phenotypic and functional characterization of effector cluster of differentiation 8 positive T cells in human patients with primary biliary cirrhosis.
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(high) CD57(+) 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(high) CD57(+) 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.
  
  
  CONCLUSIONS
  In conclusion, our data demonstrate that CD45RO(high) CD57(+) 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.
authors: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA.
authors: Masanobu
authors: M
authors: Tsuda
authors: Yoko M
authors: YM
authors: Ambrosini
authors: Weici
authors: W
authors: Zhang
authors: Guo-Xiang
authors: GX
authors: Yang
authors: Yugo
authors: Y
authors: Ando
authors: Guanghua
authors: G
authors: Rong
authors: Koichi
authors: K
authors: Tsuneyama
authors: Kosuke
authors: K
authors: Sumida
authors: Shinji
authors: S
authors: Shimoda
authors: Christopher L
authors: CL
authors: Bowlus
authors: Patrick S C
authors: PS
authors: Leung
authors: Xiao-Song
authors: XS
authors: He
authors: Ross L
authors: RL
authors: Coppel
authors: Aftab A
authors: AA
authors: Ansari
authors: Zhe-Xiong
authors: ZX
authors: Lian
authors: M Eric
authors: ME
authors: Gershwin
mesh_terms: D015703:Antigens, CD / Q000276:immunology; D001327:Autoimmune Diseases / Q000503:physiopathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016022:Case-Control Studies; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology*; D008105:Liver Cirrhosis, Biliary / Q000097:blood / Q000235:genetics / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012016:Reference Values; D018709:Statistics, Nonparametric
chemical_list: D015703:Antigens, CD; D016207:Cytokines