CD4+ T cell subsets defined by isoforms of CD45 in primary biliary cirrhosis

Abstract

Primary biliary cirrhosis (PBC) is an autoimmune condition characterized by destruction of the intrahepatic bile ducts. Autoreactive CD4+ T cells have been reported both in the peripheral circulation and in the mononuclear cell infiltrate in the affected portal tracts. In this large study we have used two- and three-colour flow cytometry to determine the phenotypes of the CD4+ T cell subsets in the peripheral blood and liver-infiltrating lymphocytes of PBC patients (n = 43), normal controls (n = 19) and patients with alcoholic cirrhosis (n = 15), according to a novel classification based on the simultaneous expression of different isoforms of CD45. In PBC patients the proportion of peripheral blood CD4+ cells possessing the CD45ROhighRA- 'memory' phenotype was significantly increased, and the CD45RO-RAhigh 'naive' population was significantly decreased, compared with the two control groups. No significant differences in peripheral blood CD4+ T cell subsets were seen between patients with pre-cirrhotic and cirrhotic PBC. A similar, but more marked, shift towards the CD45ROhighRA- 'memory' phenotype was seen in the liver-infiltrating CD4+ T cells in PBC patients compared with alcoholic cirrhotics. Cells within the CD4+ memory subpopulation were further subgrouped according to expression of CD45RB, the level of expression of which has been associated with functional differences in the memory subset. In peripheral blood no differences were seen between PBC patients and controls with respect to the proportion of CD45ROhighRBhigh and CD45ROhighRBdim memory subsets. A statistically significant difference in the distribution of these memory subsets, with an increased memory-2/memory-1 ratio was observed in the liver-infiltrating CD4+ T cells of PBC patients compared with those from alcoholic cirrhotic patients. The potential implications of this observation are discussed.