Abstract
Abnormally low CD8+ T-lymphocyte numbers is characteristic of some patients with hereditary hemochromatosis (HH), a MHC-linked disorder of iron overload. Both environmental and genetic components are known to influence CD8+ T-lymphocyte homeostasis but the role of the HH associated protein HFE is still insufficiently understood. Genome-wide expression profiling was performed in peripheral blood CD8+ T lymphocytes from HH patients selected according to CD8+ T-lymphocyte numbers and from Hfe -/- mice maintained either under normal or high iron diet conditions. In addition, T-lymphocyte apoptosis and cell cycle progression were analyzed by flow cytometry in HH patients. HH patients with low CD8+ T-lymphocyte numbers show a differential expression of genes related to lymphocyte differentiation and maturation namely CCR7, LEF1, ACTN1, NAA50, P2RY8 and FOSL2, whose expression correlates with the relative proportions of naïve, central and effector memory subsets. In addition, expression levels of LEF1 and P2RY8 in memory cells as well as the proportions of CD8+ T cells in G2/M cell cycle phase are significantly different in HH patients compared to controls. Hfe -/- mice do not show alterations in CD8+ T-lymphocyte numbers but differential gene response patterns. We found an increased expression of S100a8 and S100a9 that is most pronounced in high iron diet conditions. Similarly, CD8+ T lymphocytes from HH patients display higher S100a9 expression both at the mRNA and protein level. Altogether, our results support a role for HFE as a negative regulator of CD8+ T-lymphocyte activation. While the activation markers S100a8 and S100a9 are strongly increased in CD8+ T cells from both, Hfe -/- mice and HH patients, a differential profile of genes related to differentiation/maturation of CD8+ T memory cells is evident in HH patients only. This supports the notion that HFE contributes, at least in part, to the generation of low peripheral blood CD8+ T lymphocytes in HH.
Highlights
Hereditary hemochromatosis is a common genetic disorder of iron overload where the vast majority of patients are homozygous for the C282Y mutation in HFE, a non-classical MHCclass I gene localized on chromosome 6 in strong linkage disequilibrium with the HLA-A locus [1,2]
A very distinct picture was observed for the second cluster of functionally related genes which included: N(alpha)-acetyltransferase 50 (NAA50), purinergic receptor P2Y (G-protein coupled, 8) (P2RY8) and FOS-like antigen 2, (FOSL2) that are all up-regulated in the group of patients with a low CD8 phenotype
Both P2RY8 and FOSL2 have been implicated as regulators of cell proliferation, differentiation, and malignant transformation [23,24] and NAA50 is described as an anti-apoptotic molecule [25]
Summary
Hereditary hemochromatosis is a common genetic disorder of iron overload where the vast majority of patients are homozygous for the C282Y mutation in HFE, a non-classical MHCclass I gene localized on chromosome 6 in strong linkage disequilibrium with the HLA-A locus [1,2]. A possible explanation for the activation profile of CD8+ T cells in HH may be found in a recent work where Reuben and co-workers propose that HFE has a role in antigen processing and presentation leading to an inhibition of CD8+ T-lymphocyte activation [14]. Their studies were based on several T-lymphocyte activation read-outs in cells transfected with wild type and mutated HFE molecules, but no evidence has been provided of an effect on antigen processing and presentation functions in vivo
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