University of Oulu

Viisanen T, Gazali AM, Ihantola E-L, Ekman I, Näntö-Salonen K, Veijola R, Toppari J, Knip M, Ilonen J and Kinnunen T (2019) FOXP3+ Regulatory T Cell Compartment Is Altered in Children With Newly Diagnosed Type 1 Diabetes but Not in Autoantibody-Positive at-Risk Children. Front. Immunol. 10:19. doi: 10.3389/fimmu.2019.00019

FOXP3+ regulatory T cell compartment Is altered in children with newly diagnosed type 1 diabetes but not in autoantibody-positive at-risk children

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Author: Viisanen, Tyyne1; Gazali, Ahmad M.1; Ihantola, Emmi-Leena1;
Organizations: 1Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
2Department of Pediatrics, Turku University Hospital, Turku, Finland
3PEDEGO Research Unit, Department of Pediatrics, Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
4Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland
5Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland
6Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
7Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
8Folkhälsan Research Center, Helsinki, Finland
9Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland
10Clinical Microbiology, Turku University Hospital, Turku, Finland
11Eastern Finland Laboratory Centre (ISLAB), Kuopio, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 4.6 MB)
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Language: English
Published: Frontiers Media, 2019
Publish Date: 2020-03-27


The dysfunction of FOXP3-positive regulatory T cells (Tregs) plays a key role in the pathogenesis of autoimmune diseases, including type 1 diabetes (T1D). However, previous studies analyzing the peripheral blood Treg compartment in patients with T1D have yielded partially conflicting results. Moreover, the phenotypic complexity of peripheral blood Tregs during the development of human T1D has not been comprehensively analyzed. Here, we used multi-color flow cytometry to analyze the frequency of distinct Treg subsets in blood samples from a large cohort comprising of 74 children with newly diagnosed T1D, 76 autoantibody-positive children at-risk for T1D and 180 age- and HLA-matched control children. The frequency of CD4+CD25+CD127lowFOXP3+ Tregs was higher in children with T1D compared to control children, and this change was attributable to a higher proportion of naïve Tregs in these subjects. Further longitudinal analyses demonstrated that the increase in Treg frequency correlated with disease onset. The frequencies of the minor subsets of CD25+FOXP3low memory Tregs as well as CD25lowCD127lowFOXP3+ Tregs were also increased in children with T1D. Moreover, the ratio of CCR6-CXCR3+ and CCR6+CXCR3- memory Tregs was altered and the frequency of proliferating Ki67-positive and IFN-γ producing memory Tregs was decreased in children with T1D. The frequency of CXCR5+FOXP3+ circulating follicular T regulatory cells was not altered in children with T1D. Importantly, none of the alterations observed in children with T1D were observed in autoantibody-positive at-risk children. In conclusion, our study reveals multiple alterations in the peripheral blood Treg compartment at the diagnosis of T1D that appear not to be features of early islet autoimmunity.

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Series: Frontiers in immunology
ISSN: 1664-3224
ISSN-E: 1664-3224
ISSN-L: 1664-3224
Volume: 10
Article number: 19
DOI: 10.3389/fimmu.2019.00019
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
3121 General medicine, internal medicine and other clinical medicine
3123 Gynaecology and paediatrics
Funding: The study was supported by the Academy of Finland (Decision number 307320), the Sigrid Jusélius Foundation, State Research Funding (VTR) and the Finnish Diabetes Research Foundation. The DIPP study was supported by the Academy of Finland (Center of Excellence in Molecular Systems Immunology and Physiology Research 2012-2017, Decision No. 250114), the Sigrid Jusélius Foundation and the Juvenile Diabetes Research Foundation.
Copyright information: © 2019 Viisanen, Gazali, Ihantola, Ekman, Näntö-Salonen, Veijola, Toppari, Knip, Ilonen and Kinnunen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.