IL-18 Synergizes with IL-7 To Drive Slow Proliferation of Naive CD8 T Cells by Costimulating Self-Peptide-Mediated TCR Signals

Naive T cell populations are maintained in the periphery at relatively constant levels via mechanisms that control expansion and contraction and are associated with competition for homeostatic cytokines. It has been shown that in a lymphopenic environment naive T cells undergo expansion due, at least in part, to additional availability of IL-7. We have previously found that T cell-intrinsic deletion of TNFR-associated factor (TRAF) 6 (TRAF6 Delta T) in mice results in diminished peripheral CD8 T cell numbers. In this study, we report that whereas naive TRAF6 Delta T CD8 T cells exhibit normal survival when transferred into a normal T cell pool, proliferation of naive TRAF6 Delta T CD8 T cells under lymphopenic conditions is defective. We identified IL-18 as a TRAF6-activating factor capable of enhancing lymphopenia-induced proliferation (LIP) in vivo, and that IL-18 synergizes with high-dose IL-7 in a TRAF6-dependent manner to induce slow, LIP/homeostatic-like proliferation of naive CD8 T cells in vitro. IL-7 and IL-18 act synergistically to upregulate expression of IL-18R genes, thereby enhancing IL-18 activity. In this context, IL-18R signaling increases PI3K activation and was found to sensitize naive CD8 T cells to a model noncognate self-peptide ligand in a way that conventional costimulation via CD28 could not. We propose that synergistic sensitization by IL-7 and IL-18 to self-peptide ligand may represent a novel costimulatory pathway for LIP.