miR-182 and miR-10a Are Key Regulators of Treg Specialisation and Stability during Schistosome and Leishmania-associated Inflammation

Abstract

A diverse suite of effector immune responses provide protection against various pathogens. However, the array of effector responses must be immunologically regulated to limit pathogen- and immune-associated damage. CD4+Foxp3+ regulatory T cells (Treg) calibrate immune responses; however, how Treg cells adapt to control different effector responses is unclear. To investigate the molecular mechanism of Treg diversity we used whole genome expression profiling and next generation small RNA sequencing of Treg cells isolated from type-1 or type-2 inflamed tissue following Leishmania major or Schistosoma mansoni infection, respectively. In-silico analyses identified two miRNA “regulatory hubs” miR-10a and miR-182 as critical miRNAs in Th1- or Th2-associated Treg cells, respectively. Functionally and mechanistically, in-vitro and in-vivo systems identified that an IL-12/IFNγ axis regulated miR-10a and its putative transcription factor, Creb. Importantly, reduced miR-10a in Th1-associated Treg cells was critical for Treg function and controlled a suite of genes preventing IFNγ production. In contrast, IL-4 regulated miR-182 and cMaf in Th2-associed Treg cells, which mitigated IL-2 secretion, in part through repression of IL2-promoting genes. Together, this study indicates that CD4+Foxp3+ cells can be shaped by local environmental factors, which orchestrate distinct miRNA pathways preserving Treg stability and suppressor function.

Acute Thymic Involution and Mechanisms for Recovery

“…During Leishmania-and Schistosome-associated inflammation, miR-182 and miR-10a have been found to be main regulators of the CD4 + Foxp3 + Tregs, and the IL-12/ IFN-γ axis regulates miR-10a as well as its putative transcription factor, Creb. TGF-β is involved in the stimulation of miR-10a expression during parasitic infection (Kelada et al 2013). Blocking the TGF-β pathway slows down the age-related thymic atrophy (Hauri-Hohl et al 2008).…”

miRNAs as new molecular insights into inflammatory bowel disease: Crucial regulators in autoimmunity and inflammation

“…Treg cells can be classified into two populations, naturally-occurring Treg (nTreg) cells that are generated in the thymus, and inducible Treg (iTreg) cells that arise from naïve CD4 + precursors in the periphery [90] . miRNAs play pivotal roles in the regulation of both Treg cell development and function [93,94] . miR10a is highly expressed in nTreg cells and can be induced by retinoic acid and TGFb in iTreg cells [90] .…”

MicroRNA-93 may control vascular endothelial growth factor A in circulating peripheral blood mononuclear cells in acute Kawasaki disease

“…MiR-182 was shown to be a key effector of the suppressor activity of regulatory T-cells during an immune response (30). It has been suggested that dysfunctional regulatory T-cells are associated with immune dysfunction in KD, but the mechanisms resulting in T-cell dysfunction remain unknown.…”