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.
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