Tom Van Belle

IL-15 Augments TCR-Induced CD4+ T Cell Expansion In Vitro by Inhibiting the Suppressive Function of CD25High CD4+ T Cells

Due to its critical role in NK cell differentiation and CD8+ T cell homeostasis, the importance of IL-15 is more firmly established for cytolytic effectors of the immune system than for CD4+ T cells. The increased levels of IL-15 found in several CD4+ T cell-driven (auto-) immune diseases prompted us to examine how IL-15 influences murine CD4+ T cell responses to low dose TCR-stimulation in vitro. We show that IL-15 exerts growth factor activity on both CD4+ and CD8+ T cells in a TCR-dependent and Cyclosporin A-sensitive manner. In CD4+ T cells, IL-15 augmented initial IL-2-dependent expansion and once IL-15Rα was upregulated, IL-15 sustained the TCR-induced expression of IL-2/15Rβ, supporting proliferation independently of secreted IL-2. Moreover, IL-15 counteracts CD4+ T cell suppression by a gradually expanding CD25HighCD4+ T cell subset that expresses Foxp3 and originates from CD4+CD25+ Tregs. These in vitro data suggest that IL-15 may dramatically strengthen the T cell response to suboptimal TCR-triggering by overcoming an activation threshold set by Treg that might create a risk for autoimmune pathology.