Young-June Kim

Identification of a Novel Activation-inducible Protein of the Tumor Necrosis Factor Receptor Superfamily and Its Ligand

Among members of the tumor necrosis factor receptor (TNFR) superfamily, 4-1BB, CD27, and glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR) share a striking homology in the cytoplasmic domain. Here we report the identification of a new member, activation-inducible TNFR family member (AITR), which belongs to this subfamily, and its ligand. The receptor is expressed in lymph node and peripheral blood leukocytes, and its expression is up-regulated in human peripheral mononuclear cells mainly after stimulation with anti-CD3/CD28 monoclonal antibodies or phorbol 12-myristate 13-acetate/ionomycin. AITR associates with TRAF1 (TNF receptor-associated factor 1), TRAF2, and TRAF3, and induces nuclear factor (NF)-κB activation via TRAF2. The ligand for AITR (AITRL) was found to be an undescribed member of the TNF family, which is expressed in endothelial cells. Thus, AITR and AITRL seem to be important for interactions between activated T lymphocytes and endothelial cells.

Human 4-1BB regulates CD28 co-stimulation to promote Th1 cell responses.

Our present study provides evidence that the 4‐1BB signal is critical to CD28 co‐stimulation in maintaining T cell activation when CD28 has been down‐regulated because of repeated stimulation. The 4‐1BB signal synergized with CD28 co‐stimulation by lowering the threshold of anti‐CD28 required to sustain proliferation and IL‐2 production. The 4‐1BB signal also modulated CD28‐mediated cytokine profiles by markedly enhancing Th1 but suppressing Th2‐type cytokine production. The 4‐1BB signal generated Th1‐type cells, as identified by intracellular IFN‐γ production. IFN‐γ induction was detected preferentially in 4‐1BB‐expressing cells, but not in those expressing CD30. 4‐1BB and CD30 were induced in both CD4+ and CD8+ cells, but the location of the two molecules was mutually exclusive in each T cell subset. Our study suggests that the 4‐1BB signal regulates CD28 co‐stimulation in the targeted subset cells to favor Th1 development and maintain long‐term cell growth.

Therapeutic potential of 4-1BB (CD137) as a regulator for effector CD8(+) T cells.

A fundamental problem of antitumor immunity is tumor-induced immunosuppression. Tumor cells often down-regulate expression of co-stimulatory molecules, tumor antigens, and major histocompatibility complex (MHC) molecules on tumor cells, secrete immunosuppressive substance such as transforming growth factor-beta (TGF-beta) or interleukin-4 (IL-4), and induce apoptosis of effector T cells to escape surveillance. A major goal of antitumor or antivirus immunotherapy is to generate long-lived protective T cells that enable killing of target cells. In this review, we discuss the importance of 4-1BB for development or survival of functionally active effector CD8(+) T cells against tumors, virus infection, and allogeneic immune responses and for potential therapeutic application.

P21waf-1-Chk1 pathway monitors G1 phase microtubule integrity and is crucial for restriction point transition.

Microtubule-disruption (MTD) is often thought to arrest the mammalian cell cycle only during mitosis. However, MTD has also been demonstrated to arrest cells during interphase at a G1-phase point we call G1MTA. Microtubule integrity is now shown to be required for progression past G1MTA and the mammalian restriction-point. Neither p21waf1 nor p27kip1 are required for MTD-induced G1-arrest. Only p21waf1 is crucial for normal G1MTA passage. The p21waf1-Chk1-cdc25C-cdc2-checkpoint-pathway is implicated in monitoring this passage. P21waf1 deletion deregulates G1MTA transition and decreases MTD-G1 arrest, possibly via Chk1 disregulation. Oncogene-induced overexpression of p21waf1 produced opposite effects on the Chk1-cdc25C-cdc2 pathway and enhanced MTD-G1 arrest. G1MTA thus represents a novel facet of mammalian G1/S checkpoint. Key Words: Microtubule damage, p21waf1, Cell cycle, Restriction point, G1 phase