Heads of Laboratories
Unlike many organ systems present throughout evolution, the immune system occurs only in vertebrates. Although this places a limit on classical genetic analysis, Dr. Nussenzweig’s laboratory circumvents the problem by combining biochemistry and molecular biology with gene targeting and transgenic technologies to better understand the molecular aspects of adaptive and innate immune responses. He focuses on B lymphocytes and antibodies for adaptive immunity and on dendritic cells in his studies of innate immunity.
The function of the immune system is to protect vertebrates from a multitude of different pathogens, and there are two types of immune responses that have evolved to accomplish this task: innate and adaptive immunity. Lymphocytes are the primary effectors of adaptive immunity and assemble a diverse repertoire of immune receptors using a somatic gene recombination process known as V(D)J recombination. This process enables the production of a very large number of unique receptors that are able to recognize almost any antigen, but it also produces self-reactive receptors, which must be silenced to prevent autoimmune diseases.
A series of checkpoints has evolved to ensure that B cells emerging from the bone marrow carry functional and non-self-reactive antigen receptors. Dr. Nussenzweig’s laboratory has examined the regulation of these checkpoints and found that many depend on signals from membrane immunoglobulin. In its absence, B cells fail to pass the checkpoints and die by apoptosis. Ongoing research focuses on understanding checkpoint regulation, the mechanisms that veto autoimmune antibody production and how this breaks down in autoimmune diseases.
Although V(D)J recombination produces a multitude of antigen receptors, they are relatively low-affinity receptors that must be refined by somatic hypermutation and class switch recombination to produce the high-affinity antibodies that protect against most pathogens. The lab is investigating the molecular basis of these diversification reactions and how they can occasionally lead to cancer-associated chromosome translocations.
A second area of interest for the Nussenzweig lab is the physiological function of dendritic cells. To examine the function of dendritic cells in the steady state, he and his colleagues devised an in vivo antigen delivery system that uses a monoclonal antibody and a dendritic cell-restricted endocytic receptor, DEC-205. This route of antigen delivery is several orders of magnitude more efficient in inducing T cell activation and cell division than free peptide in strong adjuvants. But the activation response is not sustained, and T cells become unresponsive to systemic rechallenge with antigen. Coinjection with anti-CD40 agonistic antibody changes the outcome from tolerance to prolonged T cell activation and immunity, indicating that in the steady state, the primary function of dendritic cells is to maintain peripheral tolerance.
Dr. Nussenzweig’s experiments are consistent with the notion that self-antigens induce tolerance. In contrast, antigens taken up by dendritic cells in the context of activation stimuli, such as those found during inflammation or tissue destruction, induce prolonged T cell activation. This steady-state tolerizing function of dendritic cells may be essential to their role in eliciting immunity. During inflammation or infection, they present self-antigens simultaneously with non-self. By establishing tolerance to self before challenge with pathogens, dendritic cells can focus the adaptive immune system entirely on the pathogen, thereby avoiding autoimmunity. The ability to target antigens to dendritic cells and control their function in vivo has significat implications for the development of vaccines and therapies for autoimmunity. Recently, the lab defined distinct progenitor lineages for classical spleen dendritic cells, plasmacytoid dendritic cells and monocytes, a useful step toward antigen-specific targeting.
Dr. Nussenzweig received his bachelor’s degree from New York University in 1975. He received his Ph.D. in 1981 from The Rockefeller University, where he studied under Ralph M. Steinman, and his M.D. in 1982 from the New York University School of Medicine. He continued his clinical training at Massachusetts General Hospital, first as an intern and resident in internal medicine from 1982 to 1985 and then as a clinical fellow in infectious diseases from 1984 to 1985. In 1986 he began his postdoctoral research in genetics at Harvard Medical School and returned to Rockefeller in 1990 as assistant professor. He was named associate professor in 1994 and professor and senior physician in 1996. He has been an investigator at the Howard Hughes Medical Institute since 1999.
Dr. Nussenzweig was elected to the U.S. National Academy of Sciences and the Brazilian Academy of Sciences in 2011 and the Institute of Medicine in 2009. He received the Lee C. Howley Sr. Prize for Arthritis Research in 2008, the American Association of Immunologists-Huang Foundation Meritorious Career Award in 2004 and the Solomon A. Berson Alumni Achievement Award for Basic Science from New York University in 2003. He is a member of the American Academy of Arts and Sciences.
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