Date of Award
Doctor of Philosophy (PhD)
CD137, a member of the tumor necrosis factor receptor superfamily of cell surface proteins, acts as a costimulatory receptor on T cells, natural killer cells, B cell subsets, and some dendritic cells. Agonistic anti-CD137 monoclonal antibody (MAb) therapy has been combined with other chemotherapeutic agents in human cancer trials. Based on its ability to promote tumor clearance, we hypothesized that anti-CD137 MAb might activate immune responses and resolve chronic viral infections. We evaluated anti-CD137 MAb therapy in a mouse infection model of chikungunya virus (CHIKV), an alphavirus that causes chronic polyarthritis in humans and is associated with reservoirs of CHIKV RNA that are not cleared efficiently by adaptive immune responses. Analysis of viral tropism revealed that CHIKV RNA was present preferentially in splenic B cells and follicular dendritic cells during the persistent phase of infection, and animals lacking B cells did not develop persistent CHIKV infection in lymphoid tissue. Anti-CD137 MAb treatment resulted in T cell-dependent clearance of CHIKV RNA in lymphoid tissue, although this effect was not observed in musculoskeletal tissue. The clearance of CHIKV RNA from lymphoid tissue by anti-CD137 MAb was associated with reductions in the numbers of germinal center B cells and follicular dendritic cells. Similar results were observed with anti-CD137 MAb treatment of mice infected with Mayaro virus, a related arthritogenic alphavirus. Thus, anti-CD137 MAb treatment promotes resolution of chronic alphavirus infection in lymphoid tissues by reducing the numbers of target cells for infection and persistence. As a result of agonistic anti-CD137 MAb treatment, antibody responses to multiple T cell-dependent antigens including infectious virus, recombinant viral proteins, and conjugated haptens but not to a T cell-independent antigen or at homeostasis were impaired. These effects were not due to enhanced apoptosis or impaired proliferation of B cells but instead correlated with changes in lymphoid follicle structure and GC B cell dispersal, and were mediated by CD137 signaling in CD4+ and CD8+ T cells. Our experiments in mice suggest that agonistic anti-CD137 mAbs used in cancer and autoimmunity therapy may cause GC collapse and impair long-term antibody and B cell memory responses.
Chair and Committee
Michael S. Diamond
Paul M. Allen, Anthony R. French, Deborah J. Lenschow, Adrianus Boon,
Hong, Jun, "Effects of agonistic anti-CD137 antibody on chikungunya virus infection and B cell responses" (2020). Arts & Sciences Electronic Theses and Dissertations. 2199.