Interaction between Treg Apoptosis Pathways, Treg Function and HLA Risk Evolves during Type 1 Diabetes Pathogenesis

Sanja Glisic,Parthav Jailwala,Srinivasa M. Srinivasula

doi:10.1371/journal.pone.0036040

Sanja Glisic, Parthav Jailwala + Show 1 more

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https://doi.org/10.1371/journal.pone.0036040

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Abstract

We have previously reported increased apoptosis of regulatory T cells (Tregs) in recent-onset Type 1 Diabetes subjects (RO T1D) in the honeymoon phase and in multiple autoantibody-positive (Ab+) subjects, some of which are developing T1D. We have also reported that increased Treg apoptosis was associated with High HLA risk and that it subsided with cessation of honeymoon period. In this report, we present results generated using genetics, genomics, functional cell-based assays and flow cytometry to assess cellular changes at the T-cell level during T1D pathogenesis. We measured ex vivo Treg apoptosis and Treg function, surface markers expression, expression of HLA class II genes, the influence of HLA risk on Treg apoptosis and function, and evaluated contribution of genes reported to be involved in the apoptosis process. This integrated comprehensive approach uncovered important information that can serve as a basis for future studies aimed to modulate Treg cell responsiveness to apoptotic signals in autoimmunity. For example, T1D will progress in those subjects where increased Treg apoptosis is accompanied with decreased Treg function. Furthermore, Tregs from High HLA risk healthy controls had increased Treg apoptosis levels and overexpressed FADD but not Fas/FasL. Tregs from RO T1D subjects in the honeymoon phase were primarily dying through withdrawal of growth hormones with contribution of oxidative stress, mitochondrial apoptotic pathways, and employment of TNF-receptor family members. Ab+ subjects, however, expressed high inflammation level, which probably contributed to Treg apoptosis, although other apoptotic pathways were also activated: withdrawal of growth hormones, oxidative stress, mitochondrial apoptosis and Fas/FasL apoptotic pathways. The value of these results lie in potentially different preventive treatment subjects would receive depending on disease progression stage when treated.

Highlights

Type 1 Diabetes (T1D) is one of the most prevalent autoimmune chronic diseases in children with a raising incidence of,3% annually [1,2]
Our results show that T1D will progress in those subjects where increased Treg apoptosis is accompanied with decreased Treg function
histocompatibility antigens (HLA) risk associated with Treg apoptosis levels As HLA has been recognized as a major genetic risk factor, subject groups involved in this study were partitioned into two HLA risk groups (Low and High) according to the scheme we have developed earlier [30]

Summary

Introduction

Type 1 Diabetes (T1D) is one of the most prevalent autoimmune chronic diseases in children with a raising incidence of ,3% annually [1,2]. In the light of observations of increased Treg apoptosis in High HLA risk subjects compared to Low HLA risk group (Figure 1A), we were interested in the expression of genes involved in apoptosis pathways with a goal to identify potential differences in activated apoptotic pathways associated with T1D pathogenesis.

Results

Conclusion