Ganglioside GM1 deficiency in effector T cells from NOD mice induces resistance to regulatory T-cell suppression

Gusheng Wu, Zi Hua Lu, Hans Joachim Gabius, Robert W. Ledeen, David Bleich

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

OBJECTIVE - To detect GM1 deficiency and determine its role in effector T cells (Teffs) from NOD mice in establishing resistance to regulatory T-cell (Treg) suppression. RESEARCH DESIGN AND METHODS - CD4+ and CD8 + Teffs were isolated from spleens of prediabetic NOD mice for comparison with similar cells from Balb/c, C57BL/6, and NOR mice. GM1 was quantified with thin-layer chromatography for total cellular GM1 and flow cytometry for cell-surface GM1. Suppression of Teff proliferation was determined by application of GM1 crosslinking agents or coculturing with Tregs. Calcium influx in Teffs was quantified using fura-2. RESULTS - Resting and activated CD4+ and CD8+ Teffs of NOD mice contained significantly less GM1 than Teffs from the other three mouse strains tested. After activation, NOD Teffs resisted suppression by Tregs or GM1 cross-linking agents in contrast to robust suppression of Balb/c Teffs; this was reversed by preincubation of NOD Teffs with GM1. NOD Teffs also showed attenuated Ca2+ influx via transient receptor potential channel 5 (TRPC5) channels induced by GM1 cross-linking, and this, too, was reversed by elevation of Teff GM1. CONCLUSIONS - GM1 deficiency occurs in NOD Teffs and contributes importantly to failed suppression, which is rectified by increasing Teff GM1. Such elevation also reverses subthreshold Ca2+ influx via TRPC5 channels, an essential aspect of suppression. Our results also support a critical role for galectin-1 as a GM1 cross-linking counter-receptor that fittingly is upregulated and released by Tregs during activation. These findings suggest a novel mechanism by which pathogenic Teffs evade regulatory suppression, thereby leading to autoimmune β-cell destruction and type 1 diabetes.

Original languageEnglish (US)
Pages (from-to)2341-2349
Number of pages9
JournalDiabetes
Volume60
Issue number9
DOIs
StatePublished - Sep 2011

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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