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Sci Transl Med. 2017 Feb 22;9(378). pii: eaaf8848. doi: 10.1126/scitranslmed.aaf8848.

A divergent population of autoantigen-responsive CD4+ T cells in infants prior to β cell autoimmunity.

Author information

1
DFG-Center for Regenerative Therapies Dresden, Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany.
2
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, U.K.
3
Institute for Medical Informatics and Biometry, Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany.
4
Institute of Diabetes Research, Helmholtz Zentrum München, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
5
Forschergruppe Diabetes e.V., Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
6
German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
7
DFG-Center for Regenerative Therapies Dresden, Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany. ezio.bonifacio@crt-dresden.de.
8
Paul Langerhans Institute Dresden of the Helmholtz Centre Munich at the Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
9
Institute for Diabetes and Obesity, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.

Abstract

Autoimmune diabetes is marked by sensitization to β cell self-antigens in childhood. We longitudinally followed at-risk children from infancy and performed single-cell gene expression in β cell antigen-responsive CD4+ T cells through pre- and established autoimmune phases. A striking divergence in the gene signature of β cell antigen-responsive naïve CD4+ T cells from children who developed β cell autoimmunity was found in infancy, well before the appearance of β cell antigen-specific memory T cells or autoantibodies. The signature resembled a pre-T helper 1 (TH1)/TH17/T follicular helper cell response with expression of CCR6, IL21, TBX21, TNF, RORC, EGR2, TGFB1, and ICOS, in the absence of FOXP3, IL17, and other cytokines. The cells transitioned to an IFNG-TH1 memory phenotype with the emergence of autoantibodies. We suggest that the divergent naïve T cell response is a consequence of genetic or environmental priming during unfavorable perinatal exposures and that the signature will guide future efforts to detect and prevent β cell autoimmunity.

PMID:
28228602
DOI:
10.1126/scitranslmed.aaf8848
[Indexed for MEDLINE]

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