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

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.

• Authors: Anne-Kristin Heninger, Anne Eugster, Denise Kuehn, Florian Buettner, Matthias Kuhn, Annett Lindner, Sevina Dietz, Sibille Jergens, Carmen Wilhelm, Andreas Beyerlein, Anette-G Ziegler, Ezio Bonifacio
• Journal: Science translational medicine (Sci Transl Med) Vol. 9 Issue 378 (02 22 2017) ISSN: 1946-6242 [Electronic] United States
• PMID: 28228602 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017, American Association for the Advancement of Science.

Chemical References

• Autoantibodies
• Autoantigens
• Tetanus Toxin
• Glutamate Decarboxylase
• glutamate decarboxylase 2

Topics

• Autoantibodies (biosynthesis)
• Autoantigens (immunology)
• Autoimmunity (drug effects, genetics)
• CD4-Positive T-Lymphocytes (drug effects, immunology)
• Gene Expression Profiling
• Glutamate Decarboxylase (metabolism)
• Humans
• Immune Tolerance (drug effects)
• Infant
• Insulin-Secreting Cells (drug effects, immunology)
• Tetanus Toxin (pharmacology)
• Th1 Cells (immunology)
• Transcription, Genetic (drug effects)