H2-M3-restricted CD8+ T cells augment CD4+ T-cell responses by promoting DC maturation

Infection with Listeria monocytogenes triggers the activation and expansion of nonconventional CD8+ T cells restricted by the MHC class Ib molecule, H2-M3. H2-M3-restricted CD8+ T cells exhibit a memory phenotype, rapidly produce cytokines, and reach peak frequencies sooner than conventional MHC class Ia-restricted CD8+ T cells. In this study, we found that simultaneous in vivo priming of H2-M3-restricted T cells and adoptively transferred OT-II CD4+ T cells on the same DC enhances the survival of OT-II cells. Stimulation of H2-M3-restricted T cells were found to induce DC maturation resulting in costimulatory molecule upregulation and production of TH1-type cytokines, which was dependent on both cell-to-cell contact and soluble factors, particularly TNF-alpha, produced by activated H2-M3-restricted T cells. Interestingly, H2-M3-restricted T cells were more efficient than activated NK cells in inducing DC maturation. Furthermore, we found that OVA(323-339)-coated DC matured by coculturing with peptide-stimulated H2-M3-restricted T cells were more efficient in stimulating the proliferation of Ag-activated OT-II cells. This study indicates that H2-M3-restricted T cells promote immune responses by CD4+ T cells by inducing DC maturation and suggests novel mechanisms for vaccine development.