Development of Monoclonal Antibodies Specific to Either CD300A or CD300A or Both.

CD300A is a member of the CD300 immunoglobulin (Ig)-like receptor family consisting of eight molecules in humans, all of which contain one Ig-like domain in the extracellular portion. Upon binding its ligand phosphatidylserine or phosphatidylethanolamine, CD300A mediates an inhibitory signal through the immunoreceptor tyrosine-based inhibitory motif in the cytoplasmic portion. The CD300 family molecules are highly homologous to each other.

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.

Suppression of Th1 and Th17 Proinflammatory Cytokines and Upregulation of FOXP3 Expression by a Humanized Anti-DNAM-1 Monoclonal Antibody.

DNAM-1 is an activating immunoreceptor expressed on hematopoietic cells, including both CD4 and CD8 T cells, natural killer cells, and platelets. Since DNAM-1 is involved in the pathogenesis of various inflammatory diseases and cancers in humans as well as mouse models, it is a potential target for immunotherapy for these diseases. In this study, we generated a humanized neutralizing antihuman DNAM-1 monoclonal antibody (mAb), named TNAX101A, which contains an engineered Fc portion of human IgG1 to reduce Fc-mediated effector functions.

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.

CD155-Transducing Signaling through TIGIT Plays an Important Role in Transmission of Tolerant State and Suppression Capacity.

The precise mechanism of how the regulatory T cell population elicits and maintains tolerant state in activated T cells is poorly understood. To address this issue, we established an in vitro coculture system using mouse T cells and showed that tolerant state is serially passed from preinduced-tolerant T cells into new TCR-stimulated T cells across generations in a dendritic cell-independent manner. In this successive induction process of tolerant state, TIGIT was found to play an important role: TIGIT expression on induced-tolerant T cells was promoted in stimulated T cells cocultured with the tolerant cells.

Selective DNAM-1 expression on small peritoneal macrophages contributes to CD4 T cell costimulation.

Mouse peritoneal macrophages consist of two subsets: large peritoneal macrophages (LPMs) and small peritoneal macrophages (SPMs), defined as CD11bF4/80 and CD11bF4/80 cells, respectively. We reveal that SPMs, but not LPMs, have the ability to present antigens to naïve CD4 T cells. Coculture of SPMs with naïve ovalbumin (OVA) specific CD4 T cells (OT-II) in the presence of OVA peptide effectively induced CD4 T cells priming.

Physiological function of phospholipase D2 in anti-tumor immunity: regulation of CD8 T lymphocyte proliferation.

Two major phospholipase D (PLD) isozymes in mammals, PLD1 and PLD2, hydrolyze the membrane phospholipid phosphatidylcholine to choline and the lipid messenger phosphatidic acid. Although their roles in cancer cells have been well studied, their functions in tumor microenvironment have not yet been clarified. Here, we demonstrate that PLD2 in cytotoxic CD8 T cells plays a crucial role in anti-tumor immunity by regulating their cell proliferation.

TX99 Is a Neutralizing Monoclonal Antibody Against Mouse TIGIT.

T cell immunoglobulin and ITIM domains (TIGIT) is an inhibitory immunoreceptor expressed on NK cells, effector and memory T cells, and regulatory T cells (Tregs). The ligands for TIGIT are CD155 (PVR) and CD112 (PVRL2, nectin-2), which are broadly expressed on hematopoietic cells and nonhematopoietic cells. TIGIT negatively regulates antitumor responses, but promotes autoimmune reaction.

CD155 (PVR/Necl5) mediates a costimulatory signal in CD4+ T cells and regulates allergic inflammation.

Although Th1 and Th2 cells are known to be involved in allergic inflammatory diseases, the molecular mechanisms underlying their differentiation are incompletely understood. In this study, we identified CD155 as a costimulatory molecule on CD4(+) T cells. Importantly, CD155-mediated signaling induced Th1 development in both humans and mice, as evidenced by production of IFN-γ and upregulation of Tbx21 transcription; these effects were independent of IL-12 but dependent on NF-κB-induced autocrine IFN-γ that triggered positive feedback via STAT1 activation.

Increased CD112 expression in methylcholanthrene-induced tumors in CD155-deficient mice.

Tumor recognition by immune effector cells is mediated by antigen receptors and a variety of adhesion and costimulatory molecules. The evidence accumulated since the identification of CD155 and CD112 as ligands for DNAM-1 in humans and mice has suggested that the interactions between DNAM-1 and its ligands play an important role in T cell- and natural killer (NK) cell-mediated recognition and lysis of tumor cells. We have previously demonstrated that methylcholanthrane (MCA) accelerates tumor development in DNAM-1-deficient mice, and the Cd155 level on MCA-induced tumors is significantly higher in DNAM-1-deficient mice than in wild-type (WT) mice.