IL-6 and IL-1α together, but not alone, are key modulators of regulatory T cell suppressive function: insights from computational and in vitro studies. (49.11)

Abstract

Modulation of the susceptibility of effector T cells to suppression by naturally-arising regulatory T cells (Treg) influences the development of autoimmune diseases, cancer, and transplant outcome. However, our understanding of the factors that underlie this modulation is limited. We aimed to identify the inflammatory mediators that are released by innate immune cells following their exposure to danger signals, and that reduce T cell susceptibility to suppression. A CFSE-based, in vitro mouse T cell activation system was employed to quantify Treg function and to measure the influence of the supernatant of dendritic cells sampled at multiple times after stimulation with the TLR4 ligand LPS. In parallel, 24 cytokines were quantified using Luminex™ in each sample tested. ‘Principal Component Analysis’ was utilized to assess the likely role of these cytokines with the extent of Treg suppression. This analysis suggested that IL-6, IL-1α, and TNFα were possible inhibitory mediators working in synergy. Using the CFSE dilution assay, we found that no single cytokine was capable of reducing Treg suppression. However, combinations of cytokines, in particular IL-6 and IL-1α, resulted in pronounced modulation of suppression. Our results suggest that combining computation with experimentation may help to dissect the complex milieu that determines T cell susceptibility to suppression, and specifically to identify the synergy between IL-6 and IL-1α as target for immunomodulatory therapies.