Most successful vaccines have been developed empirically, with little or no immunological insights. Continued existence of this gap has been a major barrier to the successful development of rationally designed vaccines. Due to their capacity to elicit and regulate immune responses, dendritic cells (DCs) are essential to any effort for vaccine development. The study of conventional DCs (cDCs) from humans has focused on cells in blood, which comprise BDCA-1+ myeloid DCs, BDCA-2+ plasmacytoid DCs, and a small subset of BDCA-3 high, myeloid DCs. The heterogeneity among DCs is of interest because of the specialized functional properties of each DC subset. But a comprehensive model that describes cDC genesis and the origins of cDC functional diversity in humans is lacking. To address this important gap in our understanding of this essential cell type, we propose to uncover the origin of human cDCs and to determine how adjuvants or vaccines alter cDC development. The hypothesis to be tested is that human cDC development, subset distribution, and their state of activation is altered by administration of adjuvants or vaccines. We will first elucidate the origin of cDCs in humans by identifying the human pre-DCs and by determining whether there are one or two lineages of pre-DCs corresponding to the two major myeloid cDC subsets (aim 1). Second, using clinical samples from individuals treated with increasing doses of Flt3L, we will determine if FItSL administration might Improve vaccine efficacy by mobilizing cDCs and their progenitors (aim 2). Lastly, we will define if adjuvants (I.e. TLR3 and TLR4 agonists) or vaccines (I.e. FDA-approved vaccines as well as a DC-targeted vaccine) administration impacts on cDC development in humans (aim 3). Taken together, these experiments should provide a comprehensive model of cDC development both in steady state and inflammatory condition. Understanding these processes will provide important insights into vaccine design.
Conventional dendritic cells (cDCs) initiate immune responses by presenting antigen to T cells and are therefore essential to any effort for vaccine development. The proposed research aims to develop an understanding of the origin of human cDCs and to determine how adjuvants or vaccines alter cDC development In humans with the long-term goal of being able to enable rational approaches to successfully design new vaccines that relv on DCs.
| Keeffe, Jennifer R; Van Rompay, Koen K A; Olsen, Priscilla C et al. (2018) A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates. Cell Rep 25:1385-1394.e7 |
| Wu, Xianfang; Dao Thi, Viet Loan; Huang, Yumin et al. (2018) Intrinsic Immunity Shapes Viral Resistance of Stem Cells. Cell 172:423-438.e25 |
| Hernandez, Nicholas; Melki, Isabelle; Jing, Huie et al. (2018) Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency. J Exp Med 215:2567-2585 |
| Rosenberg, Brad R; Freije, Catherine A; Imanaka, Naoko et al. (2018) Genetic Variation at IFNL4 Influences Extrahepatic Interferon-Stimulated Gene Expression in Chronic HCV Patients. J Infect Dis 217:650-655 |
| Wang, Taia T; Bournazos, Stylianos; Ravetch, Jeffrey V (2018) Immunological responses to influenza vaccination: lessons for improving vaccine efficacy. Curr Opin Immunol 53:124-129 |
| Kenney, Adam D; Dowdle, James A; Bozzacco, Leonia et al. (2017) Human Genetic Determinants of Viral Diseases. Annu Rev Genet 51:241-263 |
| Bournazos, Stylianos; Ravetch, Jeffrey V (2017) Fc? Receptor Function and the Design of Vaccination Strategies. Immunity 47:224-233 |
| Robbiani, Davide F; Bozzacco, Leonia; Keeffe, Jennifer R et al. (2017) Recurrent Potent Human Neutralizing Antibodies to Zika Virus in Brazil and Mexico. Cell 169:597-609.e11 |
| Wang, Taia T; Sewatanon, Jaturong; Memoli, Matthew J et al. (2017) IgG antibodies to dengue enhanced for Fc?RIIIA binding determine disease severity. Science 355:395-398 |
| Maamary, Jad; Wang, Taia T; Tan, Gene S et al. (2017) Increasing the breadth and potency of response to the seasonal influenza virus vaccine by immune complex immunization. Proc Natl Acad Sci U S A 114:10172-10177 |
Showing the most recent 10 out of 21 publications
