Journal of clinical immunology · 2016
Expanded CD4(+) Effector/Memory T Cell Subset in APECED Produces Predominantly Interferon Gamma.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Heikkilä Nelli, Laakso Sini M, Mannerström Helga, Kekäläinen Eliisa, Saavalainen Päivi, Jarva Hanna, Arstila Tommi P
Аннотация
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.
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.