There is an increasing need for new and better vaccines, to combat both infectious and malignant disease. This need reflects an increased number of antibiotic- resistant microbes, and new infectious pathogens, as well as potential bioterror organisms. Many current treatments of malignancies rely upon nonspecific and highly toxic medications that cause serious damage to normal organs and tissue as well as malignant cells. Anti-tumor vaccines offer the promise of more specific and effective treatments that better preserve the health and life quality of patients As the Veteran population ages, there is increased incidence of cancer, as well as autoimmune and inflammatory conditions. Our central hypothesis is that understanding how immune responses are regulated by the interplay of multiple signals is key to development of effective immunotherapies, including vaccines. One of the most important sets of such interactions is between signals that activate innate immunity and those that regulate the antigen-specific adaptive immune response. Understanding these interactions is crucial both to understand how the immune response works, and to effectively manipulate immune responses. This basic immunology proposal is focused upon gaining a more complete understanding of how receptors for microbial nucleic acids interact with additional immune receptors in the activation of B lymphocytes, with the long-term goal of applying this knowledge to better strategies in vaccine development. During the current project period, we gained important mechanistic insights into interactions between innate and adaptive immune receptors in B lymphocytes. These insights were applied both to the regulation of responsiveness to signals via the toll-like receptors (TLR) of the innate immune system, and use of B cells as cellular vaccines. The work proposed for the next project period builds upon these findings to gain additional mechanistic insights and optimize B cell vaccine effectiveness. We will pursue two major experimental Aims: 1) To optimize the interaction of innate and adaptive immune receptor interactions in B cell vaccines, using both a model response to an infectious pathogen and a tumor model, and 2) To examine the interplay between signals delivered via the B cell antigen receptor, toll-like receptors, and interferon receptors in B cell activation, innate immune tolerance, and B cell vaccination.

Public Health Relevance

Cancer and infectious diseases are major challenges to Veterans'health, causing much suffering and mortality among Veterans. Improved vaccination strategies are important to prevent and alleviate these conditions. This project investigates enhancements to a new strategy of cellular vaccination, a process of removal of immune cells from the vaccine recipient, functional activation of these cells, and reintroduction of the activated cells to jump-start an immune response to tumor cells or microbes. We aim to make this process more feasible while still effective. Understanding how immune activation signals interact will lead to more effective vaccine design, via the optimal design of stimuli to use in cellular vaccination. A key focus of this project is upon obtaining a better understanding of how important immune-activating signals interact, so we can use this information to enhance efficacy of design of vaccines.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Immunology A (IMMA)
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Iowa City VA Medical Center
Iowa City
United States
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Wallis, Alicia M; Bishop, Gail A (2018) TRAF3 regulation of inhibitory signaling pathways in B and T lymphocytes by kinase and phosphatase localization. J Leukoc Biol :
Bangalore-Prakash, Pradeep; Stunz, Laura L; Mambetsariev, Nurbek et al. (2017) The oncogenic membrane protein LMP1 sequesters TRAF3 in B-cell lymphoma cells to produce functional TRAF3 deficiency. Blood Adv 1:2712-2723
Lin, Wai W; Yi, Zuoan; Stunz, Laura L et al. (2015) The adaptor protein TRAF3 inhibits interleukin-6 receptor signaling in B cells to limit plasma cell development. Sci Signal 8:ra88
Lin, Wai W; Hostager, Bruce S; Bishop, Gail A (2015) TRAF3, ubiquitination, and B-lymphocyte regulation. Immunol Rev 266:46-55
Yi, Zuoan; Stunz, Laura L; Lin, Wai Wai et al. (2014) TRAF3 regulates homeostasis of CD8+ central memory T cells. PLoS One 9:e102120
Yi, Zuoan; Lin, Wai Wai; Stunz, Laura L et al. (2014) The adaptor TRAF3 restrains the lineage determination of thymic regulatory T cells by modulating signaling via the receptor for IL-2. Nat Immunol 15:866-74
Ontiveros, Evelena P; Halwani, Ahmad; Stunz, Laura L et al. (2014) A new model of LMP1-MYC interaction in B cell lymphoma. Leuk Lymphoma 55:2917-23
Buchta, Claire M; Bishop, Gail A (2014) TRAF5 negatively regulates TLR signaling in B lymphocytes. J Immunol 192:145-50
Yi, Zuoan; Stunz, Laura L; Bishop, Gail A (2014) CD40-mediated maintenance of immune homeostasis in the adipose tissue microenvironment. Diabetes 63:2751-60
Yi, Zuoan; Lin, Wai Wai; Stunz, Laura L et al. (2014) Roles for TNF-receptor associated factor 3 (TRAF3) in lymphocyte functions. Cytokine Growth Factor Rev 25:147-56

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