Surprisingly little is known about how antigens (Ags) enter the immune system and induce B cells to produce sustained levels of neutralizing antibodies (Abs), which protect us against deadly viruses and bacteria. The major goal of this proposal is to elucidate processes required for the development of long-lived memory B cells, which are initiated after Ags are taken up by splenic dendritic cell (DC) subsets. We will define the mechanisms by which Ag targeting to marginal zone (MZ) DC and plasmacytoid DC (pDC) subsets induce the development of memory B cells and humoral immunity.
Our Aims are: 1. To define how to regulate CD4 and CD8 T cell and humoral immune responses by targeting Ags to plasmacytoid DCs in vivo using Ags coupled to monoclonal antibodies (mAbs) specific for the human CLR, BDCA2 and transgenic (Tg) mice expressing BDCA2 only on pDCs. 2. To define if and how BDCA2 signaling inhibits type I IFN production by pDCs in vivo and whether this inhibition can alter the course of a lupus-like autoimmune disease. And 3. To define how extrafollicular Ab responses are generated by targeting Ags to MZ DCs in vivo and define what signals shift extrafollicular Ab responses induced via MZ DC targeting into an immune response leading to GC formation and long-lived, high-affinity Abs. We will investigate the role of MHC class II and CD22 in MZ DC-based Ag targeting and characterize the molecular processes required for MZ DCs to activate extrafollicular TEFH cells. These studies may lead to new insights into how to induce and regulate immunologic memory, and in particular humoral immunity. They may also help advance the field of B cell biology by helping to define the in vivo pathways leading to somatic mutation in B cells and affinity maturation. The proposed studies also may lead to new Ag targeting technology useful for the creation of effective vaccines which induce strong neutralizing antibody responses against important pathogens like H5N1 pandemic FLU, HIV, and hepatitis C viruses.

Public Health Relevance

Protective immunity to pandemic influenza viruses and many other pathogens is mediated particularly by antibodies, which neutralize the infection. However, much remains to be learned about how to induce protective responses, and indeed, many vaccines still do not induce very strong, long-lasting neutralizing antibodies. This work will lead to new insights into how to deliver antigens into the immune system so that protective antibodies are induced.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI052203-10
Application #
8686706
Study Section
Innate Immunity and Inflammation (III)
Program Officer
Palker, Thomas J
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98195
Chappell, Craig P; Giltiay, Natalia V; Dresch, Christiane et al. (2014) Controlling immune responses by targeting antigens to dendritic cell subsets and B cells. Int Immunol 26:3-11
Chappell, Craig P; Giltiay, Natalia V; Draves, Kevin E et al. (2014) Targeting antigens through blood dendritic cell antigen 2 on plasmacytoid dendritic cells promotes immunologic tolerance. J Immunol 192:5789-801
Giordano, Daniela; Draves, Kevin E; Li, Chang et al. (2014) Nitric oxide regulates BAFF expression and T cell-independent antibody responses. J Immunol 193:1110-20
Chappell, Craig P; Clark, Edward A (2013) STALing B cell responses with CD22. J Clin Invest 123:2778-80
Chaplin, Jay W; Chappell, Craig P; Clark, Edward A (2013) Targeting antigens to CD180 rapidly induces antigen-specific IgG, affinity maturation, and immunological memory. J Exp Med 210:2135-46
Ma, Daphne Y; Suthar, Mehul S; Kasahara, Shinji et al. (2013) CD22 is required for protection against West Nile virus Infection. J Virol 87:3361-75
Giltiay, Natalia V; Chappell, Craig P; Sun, Xizhang et al. (2013) Overexpression of TLR7 promotes cell-intrinsic expansion and autoantibody production by transitional T1 B cells. J Exp Med 210:2773-89
Kasahara, Shinji; Clark, Edward A (2012) Dendritic cell-associated lectin 2 (DCAL2) defines a distinct CD8ýý- dendritic cell subset. J Leukoc Biol 91:437-48
Giltiay, Natalia V; Chappell, Craig P; Clark, Edward A (2012) B-cell selection and the development of autoantibodies. Arthritis Res Ther 14 Suppl 4:S1
Chappell, Craig P; Draves, Kevin E; Giltiay, Natalia V et al. (2012) Extrafollicular B cell activation by marginal zone dendritic cells drives T cell-dependent antibody responses. J Exp Med 209:1825-40

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