Source: Interfolio F180
David Nemazee
Research Focus
Self/Non-self Discrimination in the Adaptive and Innate Immune System
The major focus of my laboratory is on self/non-self discrimination and immune response in B lymphocytes, with an increasing interest in self/nonself discrimination in the innate immune response. We have extensive expertise in using molecular biology and reverse genetics to simplify or humanize the mouse immune system to ask specific research questions. In addition to our studies on immune tolerance, we have contributed to understanding of vaccinology by assessing the pathways required for adjuvant activity and the role of inhibitory Siglec receptors. A more recent interest is in generating and studying human anti-viral antibody mouse models to speed vaccine research and to explore the barriers limiting the anti-viral response to subdominant epitopes. This work has led to insights into how best to prime B cells to generate a broadly neutralizing immune response to the CD4 binding site of HIV and to the stem region of Influenza virus.
Immune tolerance in the B cell compartment
In our early studies, we made one of the first antibody transgenic mice with defined specificity. We were the first to demonstrate clonal deletion and receptor editing as mechanisms of central tolerance. We have also developed many transgenic models to facilitate the analysis of tolerance in different compartments. We were the first to demonstrate peripheral B cell deletion as a result of encounter of tissue specific antigen. Subsequent studies involved developing systems to study editing, to establish its scope and sensitivity to antigen affinity, and to elucidate its relationship to apoptosis. We have developed superantigen transgenic models allowing a unique analysis of tolerance in a wild-type immune system at different stages of development. We made novel contributions to the study of BAFF (TNFSF13b) and its role in B cell biology, which led to one of the first deep sequencing analyses of the functional organization and usage of the Ig kappa locus. We have studied the question of how, despite their ability to be tolerized by self tissue, peripheral B cells can carry out a T-independent type II response. This led to studies on escape from peripheral B cell tolerance by cross reactive foreign antigens, analysis of the TI-2 response in the absence of Tlr signaling (MyD88-/-;Trif-/- mice), and a demonstration of how the Siglec family members CD22 and Siglec G function to aid in this distinction in promoting tolerance to self tissue through its association with host sialic acids. A by-product of this research was the finding that adjuvants do not absolutely require Tlr signaling, which was a controversial view at the time, but has since become widely accepted.
Mouse models of germline-reverted broadly neutralizing antibodies for vaccine research
A more recent interest of ours is in generating and studying human anti-viral antibody mouse models to speed vaccine research and to explore issues of the barriers associated with the anti-viral response to subdominant epitopes. This work has led to new insights into how best to prime B cells to generate a broadly neutralizing immune response to the CD4 binding site of HIV Env. We are currently studying a similar model designed to facilitate evaluation of universal flu vaccines.
The roles and functions of Phospholipase D3 and D4 in antigen presenting cells
We initially identified Pld4 as a differentially expressed gene in developing B cells, but it turned out to have highest expression in plasmacytoid dendritic cells, which are the major producers of type I interferon. A major phenotype of Pld4 deficient mice are striking defects in DCs in the response to ligands of TLR7 and TLR9, which are endosomal receptors for internalized DNA and RNA. Although my laboratory had not studied DCs previously, we have had a major interest in these cells because of their importance in vaccine responses, autoimmunity and cancer immunology. We have recently determined that PLD3 and PLD4 are nucleases that regulate TLR signaling. Current studies are focused on how exactly they function and whether they can be inhibited to aid the immune system in responding to tumors.
Education
Ph.D. (Cellular and Developmental Biology), Harvard University, 198B.A. (Biochemistry), Harvard College, 1979
Professional Experience
B.A. Biochemistry, cum laude Harvard College, 1979Ph.D. Cellular and Developmental Biology, Harvard University, 1983
Scientific Member, Basel Institute for Immunology, Basel, Switzerland ,1983-89
Awards & Professional Activities
1993 Merit Award, National Institutes of Health2014 Research Career Development Award, National Institutes of Health
Selected Publications
Jardine, J. G.; Ota, T.; Sok, D.; Pauthner, M. G.; Kulp, D. W.; Kalyuzhniy, O.; Skog, P. D.; Thinnes, T. C.; Bhullar, D.; Briney, B. S.; Menis, S.; Jones, M.; Kubitz, M.; Spencer, S.; Adachi, Y.; Burton, D. R.; Schief, W. R.; Nemazee, D. Priming a broadly neutralizing antibody response to HIV-1 using a germline-targeting immunogen. Science 2015, 349, 156-161.
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Ota, T.; Doyle-Cooper, C.; Cooper, A. B.; Doores, K. J.; Aoki-Ota, M.; Le, K.; Schief, W. R.; Wyatt, R. T.; Burton, D. R.; Nemazee, D. B cells from knock-in mice expressing broadly neutralizing HIV antibody b12 carry an innocuous B cell receptor responsive to HIV vaccine candidates. Journal of Immunology 2013, 191, 3179-3185.
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Doyle-Cooper, C.; Hudson, K. E.; Cooper, A. B.; Ota, T.; Skog, P.; Dawson, P. E.; Zwick, M. B.; Schief, W. R.; Burton, D. R.; Nemazee, D. Immune tolerance negatively regulates B cells in knock-in mice expressing broadly neutralizing HIV antibody 4E10. Journal of Immunology 2013, 191, 3186-3191.
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Duong, B. H.; Ota, T.; Aoki-Ota, M.; Cooper, A. B.; Ait-Azzouzene, D.; Vela, J. L.; Gavin, A. L.; Nemazee, D. Negative selection by IgM superantigen defines a B cell central tolerance compartment and reveals mutations allowing escape. Journal of Immunology 2011, 187, 5596-5605.
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Melamed, D.; Benschop, R. J.; Cambier, J. C.; Nemazee, D. Developmental regulation of b lymphocyte immune tolerance compartmentalizes clonal selection from receptor selection. Cell 1998, 92, 173-182.
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Russell, D. M.; Dembic, Z.; Morahan, G.; Miller, J.; Burki, K.; Nemazee, D. Peripheral deletion of self-reactive b-cells. Nature 1991, 354, 308-311.
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