Category: Autoimmune neurologic diseases
Th1 regulatory T cells (Th1-Tregs) are characterized by the acquisition of pro-inflammatory cytokine secretion and reduced suppressor activity. Th1-Tregs are found at increased frequency in autoimmune diseases including type 1 diabetes and multiple sclerosis (MS). We have previously reported that in vitro stimulation with IL-12 recapitulates the functional and molecular features of MS-associated Th1-Tregs, revealing a central role for hyper-activation of the Akt pathway in their induction. TIGIT is a newly identified co-inhibitory receptor which marks Tregs that specifically control Th1 and Th17 responses. Here we report that signaling through TIGIT counteracts the action of IL-12 in inducing the Th1 program. Specifically, TIGIT signaling represses production of IFNg, T-bet expression and restores suppressor function in Tregs treated with IL-12. FoxO1 functional inhibition abolishes the protective effect of TIGIT, indicating that TIGIT signaling promotes FoxO1 nuclear localization. Consistent with this observation, signaling through TIGIT leads to a rapid suppression of Akt function and FoxO1 phosphorylation. Finally, TIGIT stimulation reduces the production of IFNg and corrects the suppressor defect of Tregs from patients with MS. Our results indicate an important role for TIGIT in controlling the functional stability of Tregs through repression of Akt, suggesting that the TIGIT pathway could be targeted for immune-modulatory therapies in human autoimmune disorders.
Liliana Lucca– Post-Doctoral Fellow, Yale School of Medicine
Pierre-Paul Axisa– Post-Doctoral Fellow, Yale School of Medicine
Emily Singer– Post-graduate Associate, Yale School of Medicine
Neal Nolan– Yale School of Medicine
Margarita Dominguez-Villar– Assistant Professor, Yale School of Medicine
David Hafler– Professor, Chair of Neurology, Yale School of Medicine