944 PHENOTYPIC AND FUNCTIONAL PLASTICITY OF CD4posCD25highCD127pos AND CD4posCD25highCD127neg T CELLS IN AUTOIMMUNE HEPATITIS

Abstract

Background and Aims: Primary sclerosing cholangitis (PSC) is a chronic liver disease characterised by progressive inflammation, fibrosis and destruction of the bile ducts. The aetiology of PSC remains enigmatic although lymphocytic infiltration in areas of portal damage suggests an autoimmune mediated disease. CD28 is an important T cell co-stimulatory molecule and CD28− T cells have been reported as being involved in several autoimmune diseases. CD28− T cells are able to produce high amounts of IFNg, resist to apoptosis and show enhanced cytolytic activity. Given this we sought to further characterise CD28− T cells in PSC. Methods: Immunohistochemistry was used to localise CD4 and CD8 subsets in human liver tissue. Liver-infiltrating mononuclear cells (LIMCs) and peripheral blood mononuclear cells (PBMCs) were isolated from normal individuals and patients with PSC. Flow cytometry was used to determine the frequency and phenotypic characteristics of CD4 and CD8 T cells in association with CD28 expression. Results: Immunohistochemical analysis revealed high CD4 and CD8 T cell infiltration in the portal areas of human PSC liver, which was much higher when compared to normal donor livers (n = 5). CD4+ and CD8+ T cells in peripheral blood of PSC patients were present at equal frequencies (ratio of CD4:CD8 1:1) whereas in PSC LIMCs an increased frequency of CD8 T cells was observed (ratio 1:1.5). CD4+CD28− T cells were present at a frequency of 5% in normal peripheral blood, 10% in PSC patients’ peripheral blood and 52% in human PSC liver. 50% of the CD8+ T cells in normal peripheral blood were CD28−. In PSC patients, in both peripheral blood and liver the frequency of CD8+CD28− T cells was 75% and 71% respectively. Conclusions: Our results show a 5-fold increase in the frequency of CD4+CD28− T cells in human PSC liver when compared to PSC patients’ peripheral blood, and an increased frequency of CD8+CD28− T cells in both peripheral blood and liver of PSC patients. Our data suggest that CD28− T cells may be involved in the pathogenesis of PSC.