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CD137-mediated signals costimulate T cells and protect them from activation-induced apoptosis; they induce curative antitumor immunity and enhance antiviral immune responses in mice. In contrast, anti-CD137 agonistic mAbs can suppress T-dependent humoral immunity and reverse the course of established autoimmune disease. These results have provided a rationale for assessing the therapeutic potential of CD137 ligands in human clinical trials. In this study, we report that a single 200-μg injection of anti-CD137 given to otherwise naive BALB/c or C57BL/6 mice led to the development of a series of immunological anomalies. These included splenomegaly, lymphadenopathy, hepatomegaly, multifocal hepatitis, anemia, altered trafficking of B cells and CD8 T cells, loss of NK cells, and a 10-fold increase in bone marrow (BM) cells bearing the phenotype of hemopoietic stem cells. These events were dependent on CD8 T cells, TNF-α, IFN-γ, and type I IFNs. BM cells up-regulated Fas, and there was a significant increase in the number of CD8+ T cells that correlated with a loss of CD19+ and Ab-secreting cells in the BM. TCR Vαβ usage was random and polyclonal among liver-infiltrating CD8 T cells, and multifocal CD8+ T cell infiltrates were resolved upon termination of anti-CD137 treatment. Anti-CD137-treated mice developed lymphopenia, thrombocytopenia, and anemia, and had lowered levels of hemoglobin and increased numbers of reticulocytes.

CD137 (4-1BB) is a member of TNFR superfamily that acts as a costimulatory receptor and plays a role in inducing T cell proliferation, effector function and apoptosis. CD137 is expressed on activated T cells and several other cell lineages e.g. dendritic cells, granulocytes, NK cells and macrophages. Agonist α-CD137 mAbs enhance T cell proliferation, eradicate tumors, suppress humoral immunity and reverse autoimmune disease. Here, we show that α-CD137 can suppress both CD4 and CD8 T cells in an LCMV Armstrong infection model. Suppression only occurs when α-CD137 is injected within 48 hrs of infection. Anti-CD137 injected, LCMV Armstrong infected mice developed elevated levels of IL-10 and prolonged TNF-α production, resulting in decreased virus-specific CD8 T cells and chronic infection like the LCMV Clone 13. By day 8 P.I., both CD4 and CD8 T cells in the treated mice underwent extensive cell death and this correlated with increased levels of TNF-α-dependent Fas and FasL expression on T cells. Anti-CD137-mediated suppression of anti-vial immunity was blocked by injection of a neutralizing anti-TNF-α into IL-10 deficient mice. T cells in LCMV infected, α-CD137 treated Fas KO mice did not undergo apoptosis and CD8 T cell responses were normal, suggesting that suppression is enforced through TNF-Fas-dependent apoptosis. The cell target of α-CD137 responsible for initiating suppression is still under investigation. Our data suggest CD137 signaling at the early stage of virus infection can negatively regulate host anti-viral immunity by inducing T cell deletion through apoptosis.