Type 1 Diabetes in STAT Protein Family Mutations: Regulating the Th17/Treg Equilibrium and Beyond

Abstract

Improvements in the immunological, molecular, and genetic technologies such as next-generation sequencing have led to an exponential increase in the number of monogenic immune dysregulatory syndromes diagnosed, where type 1 diabetes (T1D) forms part of the autoimmune manifestations. Here, we reviewed the mutations in the signal transducer and activator of transcription (STAT) protein family, namely gain-of-function (GOF) mutations in STAT1 and STAT3 as well as STAT5b deficiency, that show strong association to T1D susceptibility. The equilibrium of T-helper 17 (Th17) and regulatory T cells (Tregs) is often found altered in patients affected by STAT GOF mutations. While the increased number of Th17 cells and the concomitant decrease in Treg cells may explain T1D in STAT3 GOF patients, the reduced number of Th17 cells found in those carrying STAT1 GOF mutations added a new level of complexity on the exact role of Th17 in the pathogenesis of T1D. Here, we describe the possible mechanisms through which STAT3 and STAT1 GOF mutations may perturb the fate and function of Th17 and Tregs and explore how this may lead to the development of T1D. We propose that the study of monogenic diseases, and in particular STAT mutations, may not only improve our understanding of the function of the human immune system but also shed light onto the pathogenic mechanisms of T1D and the genetic variants that confer predisposition to the disease.

Th17/Treg-Related Transcriptional Factor Expression and Cytokine Profile in Patients With Rheumatoid Arthritis

“…SNPs at position rs3024505, rs947474, rs6580224, and rs2293607 (mutant allele) alter STAT3 binding to target genes and suggest that polymorphisms may regulate STAT3-mediated transcription by affecting the expression of factors that are significant for early Th17 cell differentiation. Besides, patients with mutations classified as "gain-of-function" in STAT3 gene had an increased Th17 frequency and a diminished number of Tregs, and this dysregulation of the immune system could explain their autoimmune diseases (49,50). Moreover, hyperactivation of STAT3 and at the same time lack of STAT5 expression in Treg cells, what was also observed in our study, may simplify the conversion of Treg cells to Th17-like cells, causing an uncontrolled inflammatory response (51,52).…”

CD4+ T-Cells With High Common γ Chain Expression and Disturbed Cytokine Production Are Enriched in Children With Type-1 Diabetes

“…Since Th17 differentiation is negatively regulated by IL-2 signaling (35), future studies will address the question if IL-17 expression is impaired in high γ c expressing T cells. This may contribute to the recent assumption that Th17 cells may be increased, but also decreased in the context of T1D (36).…”

A human mutation in STAT3 promotes type 1 diabetes through a defect in CD8+ T cell tolerance

“…Outside of the immune system and directly within pancreatic cells, STAT3 plays a role in islet development as well as insulin secretion 10,12,13 . Previous work has proposed multiple conflicting hypotheses regarding the relevant cell types involved in the development of diabetes caused by STAT3-GOF, such as an islet-intrinsic effect or perturbing the Treg / Th17 balance within the CD4+ T cell compartment 12,14,15 .…”