Effector T Cell Resistance to Suppression and STAT3 Signaling during the Development of Human Type 1 Diabetes

The Journal of Immunology : Official Journal of the American Association of Immunologists
Emmi-Leena IhantolaTuure Kinnunen

Abstract

Dysregulation of regulatory T cell (Treg)-mediated suppression and, in particular, resistance of CD4+ effector T cells (Teffs) to suppression have been implicated in the pathogenesis of human type 1 diabetes (T1D). However, the mechanistic basis behind this resistance and the time frame during which it develops in relation to the onset of clinical T1D remain unclear. In this study, we analyzed the capacity of peripheral blood Teffs isolated both from patients with T1D and from prediabetic at-risk subjects positive for multiple diabetes-associated autoantibodies (AAb+) to be suppressed by Tregs. Because STAT3 activation through IL-6 has previously been implicated in mediating Teff resistance, we also investigated the surface expression of IL-6R as well as IL-6- and TCR-mediated phosphorylation of STAT3 in T cells from our study subjects. Teff resistance to suppression was observed both in patients with newly diagnosed and long-standing T1D but not in AAb+ subjects and was shown to be STAT3 dependent. No alterations in IL-6R expression or IL-6-mediated STAT3 activation were observed in T cells from patients with T1D or AAb+ subjects. However, faster STAT3 activation after TCR stimulation without concomitant increase in IL-6 expre...Continue Reading

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Citations

Mar 14, 2019·Clinical and Experimental Immunology·M AttiasC A Piccirillo
Mar 22, 2019·Diabetes·Tania HabibUNKNOWN Type 1 Diabetes TrialNet Study Group
Nov 9, 2019·Proceedings of the National Academy of Sciences of the United States of America·Paula ArayaJoaquín M Espinosa
Jul 29, 2020·Proceedings of the National Academy of Sciences of the United States of America·Michael P CrawfordNitin J Karandikar
Jul 9, 2020·Clinical and Experimental Immunology·A Ahmed, A Vyakarnam
Jun 12, 2021·The Journal of Experimental Medicine·Jeremy T WarshauerMark S Anderson
Dec 6, 2021·The Journal of Allergy and Clinical Immunology·Céline VandammeTuomas Virtanen
Jan 14, 2022·European Journal of Immunology·Jennie H M YangUNKNOWN Immunology of Diabetes Society T-Cell Cytometry Group

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