Antigen-Specific Treg Therapy in Type 1 Diabetes – Challenges and Opportunities

Abstract

Regulatory T cells (Tregs) are key mediators of peripheral self-tolerance and alterations in their frequencies, stability, and function have been linked to autoimmunity. The antigen-specific induction of Tregs is a long-envisioned goal for the treatment of autoimmune diseases given reduced side effects compared to general immunosuppressive therapies. However, the translation of antigen-specific Treg inducing therapies for the treatment or prevention of autoimmune diseases into the clinic remains challenging. In this mini review, we will discuss promising results for antigen-specific Treg therapies in allergy and specific challenges for such therapies in autoimmune diseases, with a focus on type 1 diabetes (T1D). We will furthermore discuss opportunities for antigen-specific Treg therapies in T1D, including combinatorial strategies and tissue-specific Treg targeting. Specifically, we will highlight recent advances in miRNA-targeting as a means to foster Tregs in autoimmunity. Additionally, we will discuss advances and perspectives of computational strategies for the detailed analysis of tissue-specific Tregs on the single-cell level.

Different subpopulations of regulatory T cells in human autoimmune disease, transplantation, and tumor immunity

“… 30 , 31 These findings have stimulated advances in the clinical development of adoptive cell therapy (ACT) and targeted therapies of Tregs in the clinic, and early clinical trial results report excellent clinical safety and efficacy. 32 , 33 , 34 , 35 , 36 , 37 , 38 Moreover, antigen‐specific Tregs 25 , 39 , 40 and chimeric antigen receptors, and in genome editing Tregs‐based therapy 41 , 42 , 43 , 44 , 45 exhibited potent benefits in autoimmunity and transplantation. Hence, the identification of specific Tregs as targets is of great clinical significance.…”

Beta cell and immune cell interactions in autoimmune type 1 diabetes: How they meet and talk to each other

“…2) The use of polyclonally expanded Tregs might critically limit their therapeutic potential in T1D. Here, approaches using antigen-specific Tregs might have a greater potential to suppress autoreactive T cells in T1D and therefore stop or delay the disease progression [ 49 , 89 , 140 , 170 ]. However, so far these approaches have shown only limited success in humans and will require further research in the future.…”

Potential Therapeutic Application of Regulatory T Cells in Diabetes Mellitus Type 1

“…In mice with a deficiency in the IL-2 and IL-2R subunits, IL-2 is a crucial cytokine necessary for the induction of Foxp3 expression, differentiation of FoxP3+ Tregs in the thymus, and their maintenance with their suppressor ability in tissues [ 25 , 26 ]. IL-2 deprivation may even lead to loss of Foxp3 expression and the conversion of Tregs into pathogenic Teff cells [ 17 , 23 , 24 , 25 , 27 , 28 ]. It has been determined that the activity of Foxp3 is mainly influenced by genetic changes.…”

“…Over 96% of the CD4+CD25+CD127-/low cell population expresses the intracellular transcription factor Foxp3 [ 54 ]. Serr et al noted problems in identifying Tregs in the peripheral blood in humans, despite the cells being characterized as CD25+ CD127 low FOXP3+, due to the different degrees of activation, functionality, and lack of homogeneity in composition, e.g., the discrepant expression of CD45RA (the presence of which was associated with stronger suppressive abilities) [ 28 ].…”

“…Serr et al also demonstrated a reduced incidence of insulin-specific Tregs in the blood of children at risk of diabetes, especially at the onset of autoimmunity against pancreatic islets, while a higher percentage of these lymphocytes were associated with slower progression to clinically overt type 1 diabetes [ 28 ].…”