miRNA Regulation of T Cells in Islet Autoimmunity and Type 1 Diabetes

Abstract

Purpose of Review Regulatory T cells (Tregs) are critical contributors to immune homeostasis and their dysregulation can lead to the loss of immune tolerance and autoimmune diseases like type 1 diabetes (T1D). Recent studies have highlighted microRNAs (miRNAs) as important regulators of the immune system, by fine-tuning relevant genes in various immune cell types. In this review article, we discuss recent insights into miRNA regulation of immune tolerance and activation. Specifically, we discuss how the dysregulation of miRNAs in T cells contributes to their aberrant function and the onset of islet autoimmunity, as well as their potential as targets of novel intervention strategies to interfere with autoimmune activation. Recent Findings Several studies have shown that the dysregulation of individual miRNAs in T cells can contribute to impaired immune tolerance, contributing to onset and progression of islet autoimmunity. Importantly, the targeting of these miRNAs, including miR-92a, miR-142-3p and miR-181a, resulted in relevant effects on downstream pathways, improved Treg function and reduced islet autoimmunity in murine models. Summary miRNAs are critical regulators of immune homeostasis and the dysregulation of individual miRNAs in T cells contributes to aberrant T cell function and autoimmunity. The specific targeting of individual miRNAs could improve Treg homeostasis and therefore limit overshooting T cell activation and islet autoimmunity.

The Many Faces of CD4+ T Cells: Immunological and Structural Characteristics

“…Due to the inducible nature of Tregs in vitro, they are potential targets for immunotherapy, such as targeting of miRNAs to regulate specific Treg populations [ 208 ]. Others are trialling the use of low doses of cytokines to selectively enhance Tregs for the treatment of T1D [ 209 ] and other autoimmune and inflammatory diseases [ 210 , 211 ].…”

Parallel Multi-Omics in High-Risk Subjects for the Identification of Integrated Biomarker Signatures of Type 1 Diabetes

“…MicroRNAs (miRNA; 20–25 nucleotides) have been prolifically studied in T1D patients because of their involvement in the regulation of genes involved in the disease [ 30 , 31 ]. Other short ncRNAs, namely, small interfering RNAs (siRNA) and Piwi-interacting (P element-interacting-wimpy testis-interacting) RNAs (piRNA) have also been implicated in T1D [ 32 , 33 , 34 , 35 ], and some of them appear to have a remarkable influence on its pathogenesis. For example, fragments of the miRNA200 family promoted T1D, and their suppression prevented it in animal models [ 36 ].…”

“…The plasma levels of miRNA21 and miRNA210 were also significantly higher in the plasma and urine of T1D patients [ 40 ]. Interestingly, 27 other identified miRNAs have also been associated with the function of T regulatory (Treg) lymphocytes that protect the β cells amid the autoimmune reaction [ 35 ].…”

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

“…Using miRNA sequencing of CD4 + T cells from peripheral blood of children with or without ongoing islet autoimmunity, we were able to identify several differentially regulated miRNAs and investigated three in more detail. Specifically, we focused on miRNAs that are predicted to target negative regulators of T cell activation and could therefore potentially inhibit Treg induction [reviewed in (29)(30)(31)].…”