Lymphocyte Gene Expression Signatures from Patients and Mouse Models of Hereditary Hemochromatosis Reveal a Function of HFE as a Negative Regulator of CD8+ T-Lymphocyte Activation and Differentiation In Vivo

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.

The hemochromatosis protein HFE 20 years later: An emerging role in antigen presentation and in the immune system

“…Further support for an HFE role as a negative regulator of CD8 + T lymphocyte activation was demonstrated in another study revealing that HFE has an impact on the expression of genes associated with the differentiation, maturation and activation of CD8 + T lymphocytes, both in HH patients and in Hfe ‐deficient mice . In particular, HH patients had differential expression patterns for genes involved in the differentiation and maturation of CD8 + T memory cells, thereby affecting the homeostatic equilibrium of these cells.…”

“…In particular, HH patients had differential expression patterns for genes involved in the differentiation and maturation of CD8 + T memory cells, thereby affecting the homeostatic equilibrium of these cells. The authors proposed that the “low CD8 phenotype” in HH may be the result of a homeostatic equilibrium of cells constantly triggered to activate and differentiate into more mature effector cells .…”

Iron Metabolism in Cancer Progression

“…Several studies on HH are associated with an increase of CD8+ T cell subsets, such as regulatory CD8+/CD28− T cells, which is coupled with a decrease of CD8+/CD28+ T cells and diminished activity of cytotoxic T lymphocytes. Furthermore, the cytokine profiles in HH patients presented high levels of IL-10 and IL-4 produced by CD8+ T cell subset [100]. Recently, some studies have focused on the impact of the presence of wild-type or mutated HFE on CD8+ T lymphocytes activation.…”

The role of MHC class Ib-restricted T cells during infection

“…However, the exact nature of this deficiency is unclear, as it could be an indirect result of iron overload or a direct result of HFE regulating CD8 + T cells (Costa et al 2015; Reuben et al 2014). Interestingly, HFE is thought to impede activation via its α1 and α2 helixes by influencing MHC class I antigen processing and presentation (Reuben et al 2014).…”