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Expanded CD4+ Effector/Memory T Cell Subset in APECED Produces Predominantly Interferon Gamma

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Abstract

Purpose

Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) is a rare human autoimmune disorder caused by mutations in the AIRE (autoimmune regulator) gene. Loss of AIRE disrupts thymic negative selection and gives rise to impaired cytotoxic and regulatory T cell populations. To date, CD4+ T helper (Th) cells remain little studied. This study aims to elucidate their role in APECED pathogenesis.

Methods

Th cells were explored in ten APECED patients and ten healthy controls using cell culture assays, multiparameter flow cytometry, and transcriptome analysis.

Results

The proportions of effector/memory populations were increased while the fraction of naive cells was diminished. The naive population was abnormally activated, with an increased number of cells expressing characteristic Th1, Th2, and Th17 cytokines. No clear deviation to any Th subclass was observed, but transcriptome analysis suggested abnormalities in the Th1 cytokine interferon gamma (IFN-γ) pathway and flow cytometry showed that INF-γ had the highest expression. The augmented INF-γ signaling may promote the function of the putative pathogenic CD8+ cytotoxic population in the patients. In addition, the frequency of CD4+ recent thymic emigrants (RTEs) was decreased in the patients, and RTEs also contained cytokine-producing cells at an increased frequency.

Conclusion

These data reveal abnormalities in the Th population and suggest that they may in part be traced to premature activation already in the thymus.

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Acknowledgments

We thank T. Bazsinka from the University of Helsinki for expert technical assistance, A. Juréus from Karolinska Institute in Stockholm for tagmentation in transcriptome analysis, and S. Linnarsson from Karolinska Institute in Stockholm for comprehensive help in transcriptome analysis. This study has been supported by the MD PhD program of the University of Helsinki, the Research Foundation of the University of Helsinki, Emil Aaltonen Foundation, Jalmari and Rauha Ahokas Foundation, Finnish Medical Foundation, Novo Nordisk Foundation, and the research funds of the University of Helsinki.

Authorship Contributions

N.H. and T.P.A. designed the study, interpreted the results, and wrote the article. N.H., S.M.L., H.M., and P.S. collected and analyzed the data. E.K., S.M.L., P.S., and H.J. critically revised the article.

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Correspondence to Nelli Heikkilä.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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The authors declare no conflict of interest.

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Heikkilä, N., Laakso, S.M., Mannerström, H. et al. Expanded CD4+ Effector/Memory T Cell Subset in APECED Produces Predominantly Interferon Gamma. J Clin Immunol 36, 555–563 (2016). https://doi.org/10.1007/s10875-016-0302-5

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  • DOI: https://doi.org/10.1007/s10875-016-0302-5

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