CD 137 (4-1BB), an activation inducible T cell costimulatory receptor and member of the TNFR superfamily is expressed on activated T cells and NK cells. We have shown that a population of immature dendritic cells in the spleen, and bone marrow derived DC constitutively express CD137. In vivo, anti-CD 137-mediated costimulation markedly enhances CD8 T cell proliferation, effector function, T cell survival, and memory development. However, anti-CD 137 mAbs can suppress T-dependent humoral immunity and induce T helper anergy. This application is designed to define the conditions that lead to T cell activation versus T cell anergy, and to understand the mechanisms that drive these responses. We chose acute LCMV viral infection in C57BL/6 mice as an experimental model because it allowed the concomitant study of T cell and B cell immune responses in a single experimental system. Preliminary data described herein show that anti-CD 137 mAbs can suppress the development of all aspects of anti-LCMV immunity providing the antibody is given within 36 hours of infection. Under these conditions LCMV-infected mice developed viremia, failed to generate virus specific CTL, remained persistently infected, and produced diminished levels of T-dependent antibodies to the virus. Nevertheless, tetramer positive CD8 T cells specific for Gp33-41 or Np396-404 although nonfunctional, were detectable at frequencies well above background in the tolerant mice 100 days post-infection. Similar results were obtained with a VSV epitope expressing vaccinia virus and influenza virus (data not shown). Thus, CD8 T cell responses like CD4 T cell responses can be suppressed by anti-CD 137 mAbs but the timing of mAb administration is critical. These observations have important implications with respect to vaccine development and APC as they prepare to antigen prime T cells. Important to the interpretation of this data is the fact that induction of suppression does not occur in CD137 deficient mice into which wild type T cells are adoptively transferred. Furthermore, CD137 expression on T cells from LCMV infected mice is not apparent by real time PCR or FACS phenotyping until 72 hours post-infection. Mice injected with anti-CD137 after T cell priming has been completed more often than not develop enhanced anti-viral immunity. We provide evidence herein that anti-CD 137 mAbs exert their affect immunosuppressive effect only during antigen priming of T cells, and that the primary cellular target of anti-CD137 mAbs are not T cells, but more likely, CD137 DC. In this proposal, we wish to: (1) Determine die fate and function of immature dendritic cells following anti-CD 137-induced peripheral T cell suppression. (2) Assess whether anti-CD 137-mediated signaling in DC directly aborts immune responses by T cells, induces the generation of cytotoxic DC, Treg, or CTL. (3) Mechanistically determine how antigen-specific CD8 T cells undergo deletion in LCMV infected, anti-CD 137 treated mice. (4) Determine whether CD 137 expression on dendritic cells serves as a molecular switch for suppressing ongoing immune responses. The central hypothesis of this proposal is that CD 137 mediated signaling within the immune system can lead to enhanced T cell immunity and the establishment of T cell memory, or antigen specific T cell suppression. The decision to induce T cell activation versus suppression can be determined by the timing of CD137 signal conveyance, and the cellular target of these signals. Thus, CD 137-mediated signaling in dendritic cells suppresses T cell-mediated immunity and in LCMV infection leads T cell tolerance. In contrast, CD137 signals delivered to T cells amplifies or prolongs T cell immune responses and enhances CD8 T cell survival.
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