Inhibition of S-phase kinase-associated protein 2 (Skp2) reprograms and converts diabetogenic T cells to Foxp3 ⁺ regulatory T cells

Abstract

Autoreactive pathogenic T cells (Tpaths) and regulatory T cells (Tregs) express a distinct gene profiles; however, the genes and associated genetic/signaling pathways responsible for the functional determination of Tpaths vs. Tregs remain unknown. Here we show that Skp2, an E3 ubiquitin ligase that affects cell cycle control and death, plays a critical role in the function of diabetogenic Tpaths and Tregs. Down-regulation of Skp2 in diabetogenic Tpaths converts them into Foxp3-expressing Tregs. The suppressive function of the Tpath-converted Tregs is dependent on increased production of TGF-β/IL-10, and these Tregs are able to inhibit spontaneous diabetes in NOD mice. Like naturally arising Foxp3 + nTregs, the converted Tregs are anergic cells with decreased proliferation and activation-induced cell death. Skp2 down-regulation leads to Tpath-Treg conversion due at least in part to up-regulation of several genes involved in cell cycle control and genes in the Foxo family. Down-regulation of the cyclin-dependent kinase inhibitor p27 alone significantly attenuates the effect of Skp2 on Tpaths and reduces the suppressive function of converted Tregs; its effect is further improved with concomitant down-regulation of p21, Foxo1, and Foxo3. In comparison, Skp2 overexpression does not change Tpath function, but significantly decreases Foxp3 expression and abrogates the suppressive function of nTregs. These findings support the critical role of Skp2 in functional specification of Tpaths and Tregs, and demonstrate an important molecular mechanism mediating Skp2 function in balancing immune tolerance during autoimmune disease development.type 1 diabetes | autoimmunity | autoreactive cells

Gene Expression Analysis Reveals Novel Shared Gene Signatures and Candidate Molecular Mechanisms between Pemphigus and Systemic Lupus Erythematosus in CD4+ T Cells

“…Consistent with a previous study that examined possible related signaling pathways shared in the pathogenesis of several systemic autoimmune diseases (SAID) such as dermatomyositis, polymyositis, rheumatoid arthritis, and SLE, a subset of five viral-related differentially expressed genes (i.e., RSAD2, IFIT3, ISG15, STAT1, and EIF2AK) was detected in peripheral blood of SAID probands and their unaffected twins ( 50 ). Additionally, other genes that were identified in our study, including BCL2, OAS1, MX1, and SKP2 have been previously associated with various autoimmune diseases ( 51 – 54 ). Therefore, our findings further suggest that these common IFN signature genes are shared across multiple autoimmune diseases including pemphigus and SLE.…”

Extracellular vesicles derived from T regulatory cells suppress T cell proliferation and prolong allograft survival

“…Formation of dnIKK2-Treg-EV-converted Treg could be explained by the link coupling cell cycle regulation and Treg differentiation provided by data that human CD4 + CD25 − T cells treated with anti-CD3/anti-CD28 together with the vasoactive intestinal peptide underwent cell cycle arrest and acquired T cell suppressive activities 52 . Moreover, the down-regulation of cell cycle and Foxo family genes resulted in reprogramming and the conversion of diabetogenic autoreactive T cells to Treg that did not need cell-to-cell contact with target cells 53 , similarly to dnIKK2-Treg-EV-converted Treg here described. Furthermore, modulating cell cycle in T cells plays a role in acquired peripheral tolerance to alloantigens 54 , as Treg from cdk-2-deficient mice display enhanced immunosuppressive function and cdk-2-deficient mice failed to reject a cardiac allograft due to the presence of fewer Th1 and more Foxp3 + Treg in tolerated grafts compared to rejected grafts from wild type recipients 55 .…”

Inhibiting Skp2 E3 Ligase Suppresses Bleomycin-Induced Pulmonary Fibrosis

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