Anomalies of the CD8(+) T cell pool in haemochromatosis: HLA-A3-linked expansions of CD8(+)CD28(-) T cells

The present study consists of a phenotypic and functional characterization of peripheral blood T lymphocytes in a group of 21 patients with hereditary haemochromatosis (HH), an MHC class I-linked genetic disease resulting in iron overload, and a group of 30 healthy individuals, both HLA-phenotyped. The HH patients studied showed an increased percentage of CD8(+) CD28(-) T cells with a corresponding reduction in the percentage of CD8(+) CD28(+) T cells in peripheral blood relative to healthy blood donors. No anomalies of CD28 expression were found in the CD4(+) subset. The presence of the HLA-A3 antigen but not age accounted for these imbalances. Thus, an apparent failure of the CD8(+) CD28(+) T cell population 'to expand', coinciding with an 'expansion' of CD8(+) CD28(-) T cells in peripheral blood of HLA-A3(+) but not HLA-A3(-) HH patients was observed when compared with the respective HLA-A3-matched control group. A significantly higher percentage of HLA-DR(+) but not CD45RO(+) cells was also found within the peripheral CD8(+) T cell subset in HH patients relative to controls. Phytohaemagglutinin (PHA) stimulation of peripheral blood mononuclear cells (PBMC) for 5 days showed: (i) that CD8(+) CD28(+) T cells both in controls and HH were able to expand in vitro; (ii) that CD8(+) CD28(-) T cells decreased markedly after activation in controls but not in HH patients. Moreover, functional studies showed that CD8(+) cytotoxic T lymphocytes (CTL) from HH patients exhibited a diminished cytotoxic activity (approx. two-fold) in standard Cr-51-release assays when compared with CD8(+) CTL from healthy controls. The present results provide additional evidence for the existence of phenotypic and functional anomalies of the peripheral CD8(+) T cell pool that may underlie the clinical heterogeneity of this iron overload disease. They are of particular relevance given the recent discovery of a novel mutated MHC class I-like gene in HH.