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

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 CD4(+) 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 alpha4beta7 in PBMC 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 alpha4beta7, 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 TCR 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 MHC class I epitope of PDC-E2. 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.