Dendritic cells (DCs), unique antigen-presenting cells (APCs) with potent T cell stimulatory capacity, direct the activation and differentiation of T cells by providing costimulatory signals. As such, they are critical regulators of both natural and vaccine-induced immune responses. A new B7 family member, B7-DC, whose expression is highly restricted to DCs, was identified among a library of genes differentially expressed between DCs and activated macrophages. B7-DC fails to bind the B7.1/2 receptors CD28 and cytotoxic T lymphocyte–associated antigen (CTLA)-4, but does bind PD-1, a receptor for B7-H1/PD-L1. B7-DC costimulates T cell proliferation more efficiently than B7.1 and induces a distinct pattern of lymphokine secretion. In particular, B7-DC strongly costimulates interferon γ but not interleukin (IL)-4 or IL-10 production from isolated naive T cells. These properties of B7-DC may account for some of the unique activity of DCs, such as their ability to initiate potent T helper cell type 1 responses.

Purpose: Human Vα24 natural killer T (NKT) cells bearing an invariant Vα24JαQ antigen receptor, the counterpart of murine Vα14 NKT cells, are activated by a specific ligand, α-galactosylceramide (αGalCer, KRN7000), in a CD1d-dependent manner. I.v. administration of αGalCer-pulsed dendritic cells (DC) induces significant activation and expansion of Vα14 NKT cells in the lung and resulting potent antitumor activities in mouse tumor metastatic models. We did a phase I dose escalation study with αGalCer-pulsed DCs in lung cancer patients. Experimental Design: Patients with advanced non–small cell lung cancer or recurrent lung cancer received i.v. injections of αGalCer-pulsed DCs (level 1: 5 × 107/m2; level 2: 2.5 × 108/m2; and level 3: 1 × 109/m2) to test the safety, feasibility, and clinical response. Immunomonitoring was also done in all completed cases. Results: Eleven patients were enrolled in this study. No severe adverse events were observed during this study in any patient. After the first and second injection of αGalCer-pulsed DCs, dramatic increase in peripheral blood Vα24 NKT cells was observed in one case and significant responses were seen in two cases receiving the level 3 dose. No patient was found to meet the criteria for partial or complete responses, whereas two cases in the level 3 group remained unchanged for more than a year with good quality of life. Conclusions: In this clinical trial, αGalCer-pulsed DC administration was well tolerated and could be safely done even in patients with advanced disease.

One of the important mechanisms of immunosuppression in the tumor-bearing status has been attributed to the down-modulation of the CD3 chain and its associated signaling molecules in T cells. Thus, the mechanism of the disappearance of CD3 was investigated in tumorbearing mice (TBM). The decrease of CD3 was observed both in the cell lysate and intact cells. Direct interaction of T cells with macrophages from TBM (TBM-macrophages) induced the decrease of CD3, and depletion of macrophages rapidly restored the CD3 expression. We found that treatment of such macrophages with N-acetylcysteine, known as antioxidant compound, prevented the decrease of CD3. Consistent with this result, the addition of oxidative reagents such as hydrogen peroxide and diamide induced the decrease of CD3 expression in T cells. Consequently, the loss of CD3 resulted in suppression of the antigen-specific T-cell response. These results demonstrate that oxidative stress by macrophages in tumorbearing status induces abnormality of the T-cell receptor complex by cell interactions with T cells. Therefore, our findings suggest that oxidative stress contributes to the regulation of the expression and function of the T-cell receptor complex.There has been great progress in the study of immunity against tumor by identification and cloning of tumor antigens (1-4) and by elucidation of the function of T-cell costimulation for antitumor responses (5-7). In spite of these advances for helping antitumor immune responses, it is known that T cells from cancer patients or tumor-bearing mice (TBM) are in a suppressed state and exhibit poor immune responses. Therefore, it is most important for tumor immunity to overcome such immunosuppression in the tumor-bearing status. Several different mechanisms have accounted for this suppression, including down-regulation of growth factors (8, 9), production of immunosuppressive cytokines (8)(9)(10)(11)(12)(13)(14), and contributions by suppressive macrophages and suppressive T cells (13,15,16). Recently, it has been shown that T cells from patients with advanced cancer or TBM have abnormal structure of the T-cell receptor (TCR)-CD3 complex, particularly the disappearance of the CD3 chain (17-22). The disappearance of CD3 in tumor-bearing status appears to be related to the proliferative response of T cells (17), and the degree of the decrease of CD3 seems to be correlated with the progression of tumor in cancer patients (18)(19)(20)22) and TBM (21).We have shown (21) that the disappearance of CD3 was due to the regulation at the protein level and was induced by interaction with macrophage (MØ)-like cells accumulated in the spleen of TBM. We found that these MØs were the same cells that have been known for a long time as ''suppressive macrophages'' in tumor-bearing status. These MØs secrete various immunosuppressive cytokines such as tumor necrosis factor, transforming growth factor ␤, interleukin 6, and prostaglandin (9,(12)(13)(14)23). In addition, these cells also express a down-regulated level of major histo...

Interaction between dendritic cells (DCs) and T cells is a prerequisite for the initiation of a T cell response. The molecular nature of this interaction remains to be fully characterized. We report in this work that freshly isolated mouse splenic DCs and bone marrow-derived DCs express CD137 on the cell surface and in soluble form. Triggering CD137 increased the secretion of IL-6 and IL-12 from DCs. More importantly, infusion of an agonistic mAb to CD137 into naive mice enhanced the ability of DCs to stimulate T cell proliferation in response to both alloantigens and a nominal Ag in vitro. This enhancement of DC function is not mediated through activation of T cells, because the effect was also observed in RAG-1 knockout mice that lack T cells. Our findings implicate CD137 as an important receptor involved in the modulation of DC function.