ANOMALIES OF THE CD8(-CELL POOL IN HEMOCHROMATOSIS - HLA-A3-LINKED EXPANSIONS OF CD8(+)CD28(-) T-CELLS() T)

The present study consists of a phenotypic and functional characteriza tion of peripheral blood T lymphocytes in a group of 21 patients with hereditary haemochromatosis (HH), an MHC class I-linked genetic diseas e resulting in iron overload, and a group of 30 healthy individuals, b oth HLA-phenotyped. The HH patients studied showed an increased percen tage of CD8(+) CD28(-) T cells with a corresponding reduction in the p ercentage of CD8(+) CD28(+) T cells in peripheral blood relative to he althy blood donors. No anomalies of CD28 expression were found in the CD4(+) subset. The presence of the HLA-A3 antigen but not age accounte d 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-mat ched control group. A significantly higher percentage of HLA-DR(+) but not CD45RO(+) cells was also found within the peripheral CD8(+) T cel l 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 a ble to expand in vitro; (ii) that CD8(+) CD28(-) T cells decreased mar kedly after activation in controls but not in HH patients. Moreover, f unctional studies showed that CD8(+) cytotoxic T lymphocytes (CTL) fro m HH patients exhibited a diminished cytotoxic activity (approx. two-f old) in standard Cr-51-release assays when compared with CD8(+) CTL fr om healthy controls. The present results provide additional evidence f or the existence of phenotypic and functional anomalies of the periphe ral CD8(+) T cell pool that may underlie the clinical heterogeneity of this iron overload disease. They are of particular relevance given th e recent discovery of a novel mutated MHC class I-like gene in HH.