The Role of Regulatory T Cell Dysregulation in the Development of Autoimmune Diseases

Background: The regulatory T cells (Tregs), especially theCD4⁺ CD25^hi CD127^lo FOXP3⁺ Tregs subpopulation is principal in the process of ensuring the immune toleration and prevention of autoimmune diseases. Their impaired frequency, stability of phenotype, or inability to suppress has increasingly been argued to contribute to the pathogenesis of autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). Nevertheless, a comparative study of Treg changes in the group of diseases is not comprehensive.

Objective: This analysis was supposed to compare the rate, performance, cytokine release, and transcriptional response of Tregs in patients with SLE, RA, and MS and how the above referred parameters relate with disease activity indicators.

Methods: The study was implemented in a form of a case-control analysis, with 90 patients (30 of each disease group) and 30 control healthy subjects. Tregs were analyzed during flow cytometry by obtaining peripheral blood mononuclear cells. Such suppressive activity was determined through co-culture assays with CFSE. The quantity of IL-35 and TGF-beta 1 was determined by ELISA and transcriptional expression of Foxp3, Helios, Lymphocyte Activation Gene-3) LAG-3(, and CD-25 was analyzed by quantitative PCR. Validated indices were used to evaluate the clinical disease activity (SLEDAI-2K, DAS 28-CRP, EDSS).

Results:  All the autoimmune disease groups had significant reductions in Tregs frequency and absolute number as compared to the control, with the most drastic reduced seen in SLE. Patient derived Tregs had a significant functional defect in the suppression of T cell effectors, especially in SLE and RA. The concentrations of IL-35 and TGF-β1 were tightly in plasma and co-culture supernatant and the difference was significant in all disease groups. qPCR showed important downregulations in the expression of FOXP3 and Helios in autoimmune patients. High negative associations between parameters of Tregs and scores on disease activity were established. Multivariate regression found that the amount of FOXP3 expression, IL-35 levels and the ability to suppress were the disparate predictors of the disease severity.

Conclusion:  The findings show that Treg dysregulation was a common immunopathological phenomenon of many autoimmune diseases, including numerical paucity, defective suppressive activity and transcriptional instability. The results presented suggest possible use of Treg-identifying markers as both diagnostic and prognostic indicators and eventually the emergence of radical therapeutic approaches geared at the regeneration of immune tolerance in autoimmune disorders, which is Treg-based.