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Eur J Immunol. 2019 May 25. doi: 10.1002/eji.201948094. [Epub ahead of print]

Peptidase inhibitor 16 identifies a human regulatory T-cell subset with reduced FOXP3 expression over the first year of recent onset type 1 diabetes.

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Molecular Immunology, Robinson Research Institute, University of Adelaide, SA, Australia.
Department of Gastroenterology, Women's and Children's Hospital, SA, Australia.
Cooperative Research Centre for Biomarker Translation, La Trobe University Research and Development Park, Bundoora, Melbourne, Australia.
Robinson Research Institute, University of Adelaide, SA, Australia.
Bioinformatics Hub, School of Biological Sciences, University of Adelaide, SA, Australia.
Benaroya Research Institute, Seattle, WA, USA.


CD4+ T-cell subsets play a major role in the host response to infection, and a healthy immune system requires a fine balance between reactivity and tolerance. This balance is in part maintained by regulatory T cells (Treg), which promote tolerance, and loss of immune tolerance contributes to autoimmunity. As the T cells which drive immunity are diverse, identifying and understanding how these subsets function requires specific biomarkers. From a human CD4 Tconv/Treg cell genome wide analysis we identified peptidase inhibitor 16 (PI16) as a CD4 subset biomarker and we now show detailed analysis of its distribution, phenotype and links to Treg function in type 1 diabetes. To determine the clinical relevance of Pi16 Treg, we analysed PI16+ Treg cells from type 1 diabetes patient samples. We observed that FOXP3 expression levels declined with disease progression, suggesting loss of functional fitness in these Treg cells in Type 1 diabetes, and in particular the rate of loss of FOXP3 expression was greatest in the PI16+ve Treg. We propose that PI16 has utility as a biomarker of functional human Treg subsets and may be useful for tracking loss of immune function in vivo. The ability to stratify at risk patients so that tailored interventions can be applied would open the door to personalised medicine for Type 1 diabetes.


FOXP3; PI16; regulatory T cells; type 1 diabetes


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