The 4-1BB receptor (CDw137), a member of the tumor necrosis factor receptor superfamily, has been shown to costimulate the activation of T cells. Here we show that anti–mouse 4-1BB monoclonal antibodies (mAbs) inhibit thymus-dependent antibody production by B cells. Injection of anti–4-1BB mAbs into mice being immunized with cellular or soluble protein antigens induced long-term anergy of antigen-specific T cells. The immune response to the type II T cell–independent antigen trinintrophenol-conjugated Ficoll, however, was not suppressed. Inhibition of humoral immunity occurred only when anti–4-1BB mAb was given within 1 wk after immunization. Anti–4-1BB inhibition was observed in mice lacking functional CD8+ T cells, indicating that CD8+ T cells were not required for the induction of anergy. Analysis of the requirements for the anti–4-1BB–mediated inhibition of humoral immunity revealed that suppression could not be adoptively transferred with T cells from anti–4-1BB–treated mice. Transfer of BALB/c splenic T cells from sheep red blood cell (SRBC)-immunized and anti–4-1BB–treated mice together with normal BALB/c B cells into C.B-17 severe combined immunodeficient mice failed to generate an anti-SRBC response. However, B cells from the SRBC-immunized, anti–4-1BB–treated BALB/c mice, together with normal naive T cells, exhibited a normal humoral immune response against SRBC after transfer, demonstrating that SRBC-specific B cells were left unaffected by anti–4-1BB mAbs.

Systemic lupus erythematosus (SLE) is a CD4+ T cell–dependent, immune complex–mediated, autoimmune disease that primarily affects women of childbearing age. Generation of high-titer affinity-matured IgG autoantibodies, specific for double-stranded DNA and other nuclear antigens, coincides with disease progression. Current forms of treatment of SLE including glucocorticosteroids are often inadequate and induce severe side effects. Immunological approaches for treating SLE in mice using anti-CD4 mAb’s or CTLA4-Ig and anti-CD154 mAb’s have proven to be effective. However, like steroid treatment, these regimens induce global immunosuppression, and their withdrawal allows for disease progression. In this report we show that lupus-prone NZB × NZW F1 mice given three injections of anti-CD137 (4-1BB) mAb’s between 26 and 35 weeks of age reversed acute disease, blocked chronic disease, and extended the mice’s lifespan from 10 months to more than 2 years. Autoantibody production in recipients was rapidly suppressed without inducing immunosuppression. Successful treatment could be traced to the fact that NZB × NZW F1 mice, regardless of their age or disease status, could not maintain pathogenic IgG autoantibody production in the absence of continuous CD4+ T cell help. Our data support the hypothesis that CD137-mediated signaling anergized CD4+ T cells during priming at the DC interface

Metablastin, also called P19, stathmin, prosolin, Lap18, and oncoprotein18, is a highly conserved cytosolic protein that undergoes extracellular factor-and cell cycle-regulated serine phosphorylation and developmentally regulated expression in mammals. It has been implicated in a variety of cellular functions including growth and differentiation, and recent evidence suggests an involvement in cell cycle control. To explore its potential role in mammalian development, we have disrupted the gene encoding metablastin by gene targeting in mice. The metablastin null mutants have no overt phenotype regarding development, growth rate, behavior, T cell maturation, or fertility and do not exhibit an increased predisposition to tumors. SCG10, a protein closely related in structure to metablastin, shows no compensatory up-regulation in metablastin ؊/؊ mice. Although the data suggest that metablastin is not essential for mammalian development, the knockout mice should prove valuable in exploring the role of this protein in cell cycle regulation.Metablastin is a 148-amino acid cytosolic phosphoprotein that has also been referred to as P19 (1), stathmin (2), prosolin (3), Lap18 (4), and oncoprotein 18 (5). Metablastin undergoes serine phosphorylation in a variety of cultured mammalian cell lines in response to a diverse group of extracellular factors. These include peptide hormones that increase in the cellular level of cAMP, factors that activate protein kinase C, agents that promote cellular calcium fluxes, T cell receptor agonists, growth factors that bind to tyrosine kinase receptors, and heat shock (1, 6 -15). In addition, phosphorylation of metablastin fluctuates during the cell cycle (16 -18). The protein kinases most strongly implicated as direct effectors of phosphorylation of metablastin in vitro and in intact cells include cyclic AMPdependent protein kinase (9, 13), calcium/calmodulin-dependent kinase Gr (12), mitogen-activated protein kinases (14, 19), and cyclin-dependent kinases (13, 18). Distinct phosphorylation sites for these kinases have been identified (11-14, 18 -20).Another interesting feature of metablastin is that it is transiently expressed, at high levels, in many, if not all, cell lineages during mammalian development, and that its level declines dramatically during terminal differentiation (21-25). The most abundant expression has been observed in young, postmitotic neuroectodermal cells (24, 25) and in male germ cells undergoing meiosis (23). Expression is also strongly induced in lymphocytes during mitogenic stimulation in vitro (3,(25)(26)(27) and in hepatocytes during liver regeneration in vivo (25,28,29). Although its function is still unknown, metablastin has been implicated in the control of a variety of cellular processes including cell growth and differentiation (17, 25, 30 -34). Recent studies suggest that phosphorylation of metablastin may be involved in the control of the G 2 /M transition of the cell cycle (33, 35).The gene encoding metablastin has been highly conserved in vertebrates (...

The human immunodeficiency virus (HIV) binds to CD4-positive cells through interaction of its envelope glycoprotein (gp120) with the CD4 molecule. CD4 is a prominent immunoregulatory molecule, and chronic exposure to antibody against CD4 (anti-CD4) has been shown to cause immunodeficiency in mice. T cell-dependent in vitro immune responses can also be inhibited by anti-CD4. Experimental findings reported here indicate that CD4-bound gp120 attracts gp120-specific antibodies derived from the blood of HIV-seropositive individuals to form a trimolecular complex with itself and CD4. Thus targeted to CD4, the gp120-specific antibody functions as an antibody to CD4; it cross-links and modulates the CD4 molecules and suppresses the activation of T cells as measured by mobilization of intracellular calcium (Ca2i+). The synergism between gp120 and anti-gp120 in blocking T cell activation occurs at low concentrations of both components. Neither gp120 nor anti-gp120 inhibits T cell activation by itself in the concentrations tested.

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