FOXP3+ Regulatory T Cell Compartment is Altered in Children with Newly Diagnosed Type 1 Diabetes but not in Autoantibody-Positive At-Risk Children

Background: FOXP3-positive regulatory T cells (Tregs) are important for maintaining peripheral immune tolerance. Multiple lines of evidence suggest that the dysfunction of 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 Tregs has not been comprehensively addressed during the development of human T1D.

Methods: We characterized the Treg compartment in a clinical cohort of 74 children with newly diagnosed T1D, 76 autoantibody-positive at-risk children and 180 age-matched autoantibody-negative control children. Using multi-color flow cytometry, we analyzed the frequencies of total, naïve and memory Tregs, as well as the expression of chemokine receptors, proinflammatory cytokines and the proliferation marker Ki67 on these Treg subsets.

Results: We observed that 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 this increase correlated with disease onset but not with the number of autoantibodies at the onset of disease. 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 (Tfr) 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.

Conclusion: Our study reveals multiple changes in the Treg compartment at the diagnosis of clinical T1D that appear not to be features of earlier islet autoimmunity.