G307S DNAM-1 Mutation Exacerbates Autoimmune Encephalomyelitis via Enhancing CD4+ T Cell Activation.

Although rs763361, which causes a nonsynonymous glycine-to-serine mutation at residue 307 (G307S mutation) of the DNAX accessory molecule-1 (DNAM-1) immunoreceptor, is a single-nucleotide polymorphism associated with autoimmune disease susceptibility, little is known about how the single-nucleotide polymorphism is involved in pathogenesis. In this study, we established human CD4+ T cell transfectants stably expressing wild-type (WT) or G307S DNAM-1 and showed that the costimulatory signal from G307S DNAM-1 induced greater proinflammatory cytokine production and cell proliferation than that from wild-type DNAM-1. The G307S mutation also enhanced the recruitment of the tyrosine kinase Lck and augmented p-Tyr322 of DNAM-1.

G307S DNAM-1 Mutation Exacerbates Autoimmune Encephalomyelitis via Enhancing CD4 T Cell Activation.

Although rs763361, which causes a nonsynonymous glycine-to-serine mutation at residue 307 (G307S mutation) of the DNAX accessory molecule-1 (DNAM-1) immunoreceptor, is a single-nucleotide polymorphism associated with autoimmune disease susceptibility, little is known about how the single-nucleotide polymorphism is involved in pathogenesis. In this study, we established human CD4 T cell transfectants stably expressing wild-type (WT) or G307S DNAM-1 and showed that the costimulatory signal from G307S DNAM-1 induced greater proinflammatory cytokine production and cell proliferation than that from wild-type DNAM-1. The G307S mutation also enhanced the recruitment of the tyrosine kinase Lck and augmented p-Tyr of DNAM-1.

DNAM-1 promotes inflammation-driven tumor development via enhancing IFN-γ production.

DNAM-1 is an activating immunoreceptor on T cells and natural killer (NK) cells. Expression levels of its ligands, CD155 and CD112, are up-regulated on tumor cells. The interaction of DNAM-1 on CD8+ T cells and NK cells with the ligands on tumor cells plays an important role in tumor immunity.

DNAM-1 regulates Foxp3 expression in regulatory T cells by interfering with TIGIT under inflammatory conditions.

Regulatory T (Treg) cells that express forkhead box P3 (Foxp3) are pivotal for immune tolerance. Although inflammatory mediators cause Foxp3 instability and Treg cell dysfunction, their regulatory mechanisms remain incompletely understood. Here, we show that the transfer of Treg cells deficient in the activating immunoreceptor DNAM-1 ameliorated the development of graft-versus-host disease better than did wild-type Treg cells.

Tumor-derived soluble CD155 inhibits DNAM-1-mediated antitumor activity of natural killer cells.

CD155 is a ligand for DNAM-1, TIGIT, and CD96 and is involved in tumor immune responses. Unlike mouse cells, human cells express both membranous CD155 and soluble CD155 (sCD155) encoded by splicing isoforms of CD155. However, the role of sCD155 in tumor immunity remains unclear.