The WT hemochromatosis protein HFE inhibits CD8+ T‐lymphocyte activation

Reuben, Alexandre; Phénix, Mikaël; Santos, Manuela M.; Lapointe, Réjean

doi:10.1002/eji.201343955

Cited by 21Iron Metabolism and DisordersT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

The WT hemochromatosis protein HFE inhibits CD8+ T‐lymphocyte activation

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Reuben, Alexandre, Phénix, Mikaël, Santos, Manuela M., Lapointe, Réjean·2014·European Journal of Immunology

DOI 10.1002/eji.201343955

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Abstract

MHC class I (MHC I) antigen presentation is a ubiquitous process by which cells present endogenous proteins to CD8(+) T lymphocytes during immune surveillance and response. Hereditary hemochromatosis protein, HFE, is involved in cellular iron uptake but, while structurally homologous to MHC I, is unable to bind peptides. However, increasing evidence suggests a role for HFE in the immune system. Here, we investigated the impact of HFE on CD8(+) T-lymphocyte activation. Using transient HFE transfection assays in a model of APCs, we show that WT HFE (HFEWT ), but not C282Y-mutated HFE, inhibits secretion of MIP-1β from antigen-specific CD8(+) T lymphocytes. HFEWT expression also resulted in major decreases in CD8(+) T-lymphocyte activation as measured by 4-1BB expression. We further demonstrate that inhibition of CD8(+) T-lymphocyte activation was independent of MHC I surface levels, β2-m competition, HFE interaction with transferrin receptor, antigen origin, or epitope affinity. Finally, we identified the α1-2 domains of HFEWT as being responsible for inhibiting CD8(+) T-lymphocyte activation. Our data imply a new role for HFEWT in altering CD8(+) T-lymphocyte reactivity, which could modulate antigen immunogenicity.

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The presence of wildtype HFE but not its mutated version on antigen presenting cells inhibits the activation of CD8+ T cells.
“Some of these observations may be attributable to the fact that the presence of wildtype HFE but not its mutated version on antigen presenting cells (APC) inhibits the activation of CD8 + T cells (Reuben et al., 2014).”
From Iron in infection and immunity (2020) · cites this paper as Reuben et al., 2014
The Abstract reports that wild-type HFE, but not the C282Y mutant, inhibited CD8+ T-cell activation in a model of antigen-presenting cells. The Discussion qualifies the broader reference to a “mutated version”: the H63D mutant showed an intermediate T-cell inhibition profile, so the finding does not apply to all HFE mutants. (LLM, conf=0.88)
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RESEARCH ARTICLE 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
Costa, M., Cruz, E., Oliveira, S., Benes, V., Ivacevic, T., Silva, M. J., Vieira, I., Dias, F., Fonseca, S., Gonçalves, M. M. D. S. L. B., et al. (2016)
Loss of central and peripheral CD 8+ T ‐cell tolerance to HFE in mouse models of human familial hemochromatosis
Boucherma, R., Kridane‐Miledi, H., Vives, F. L., Vauchy, C., Borg, C., Kleinclauss, F., Fiette, L., Tiberghien, P., Lemonnier, F. A., Rohrlich, P., et al. (2012) · European Journal of Immunology · doi:10.1002/eji.201141664 · Cited by 5 · see citing works
IMMUNOBIOLOGY HFE cross-talks with the MHC class I antigen presentation pathway
Almeida, S. F. D., Carvalho, I. F., Cardoso, C. S., Cordeiro, J. V., Azevedo, J. E., Neefjes, J., & de Sousa, M. A. B. (2016)
HFE cross-talks with the MHC class I antigen presentation pathway
de Almeida, S. F., Fidalgo-Carvalho, I., Cardoso, C. S. D. F. L. P., Cordeiro, J. V., Azevedo, J. E., Neefjes, J., & de Sousa, M. A. B. (2005) · Blood · doi:10.1182/blood-2004-12-4640 · Cited by 60 · see citing works

Authors: Reuben, A., Phénix, M., Santos, M. M., & Lapointe, R.
Affiliations: Centre Hospitalier de l’Université de Montréal (CA)
Corresponding author: Santos, Manuela M.
Lapointe, Réjean
ORCID: Reuben, Alexandre
Santos, Manuela M.
Lapointe, Réjean
Venue: European Journal of Immunology
Publisher: Wiley
Published: 2014-03-20
Volume: 44
Issue: 6
Pages: 1604-1614
ISSN: 0014-2980 (ISSN-L)
1521-4141
DOI: 10.1002/eji.201343955
OpenAlex: W1907239252
Cited by: 21
References: 51
Citations by year: 2026: 2 · 2025: 1 · 2024: 2 · 2021: 2 · 2020: 4 · 2019: 1 · 2017: 4 · 2016: 1 · 2015: 3 · 2014: 1
FWCI: 2.11
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: European Journal of Immunology (publishedVersion)
PubMed (publishedVersion)
Funders: Université de Montréal
Canadian Institutes of Health Research (MOP123246)
Natural Sciences and Engineering Research Council of Canada (298515-2011)
Topics: Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords: HFE gene, hereditary hemochromatosis, CD8+ T cell activation, MHC class I antigen presentation, C282Y mutation, MIP-1β, 4-1BB, antigen immunogenicity, antigen-presenting cells, iron metabolism
MeSH terms: Hemochromatosis Protein, Gene Expression Regulation, Humans, Lymphocyte Activation, Membrane Proteins, Histocompatibility Antigens Class I, Protein Structure, Tertiary, CD8-Positive T-Lymphocytes, Amino Acid Substitution, Mutation, Missense, Tumor Necrosis Factor Receptor Superfamily, Member 9, HEK293 Cells

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The WT hemochromatosis protein HFE inhibits CD8+ T‐lymphocyte activation

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