Heads of Laboratories
Investigator, Howard Hughes Medical Institute
Zanvil A. Cohn and Ralph M. Steinman Professor
Laboratory of Molecular Immunology
Dr. Nussenzweig’s laboratory studies molecular aspects of the immune system’s innate and adaptive responses, using a combination of biochemistry, molecular biology, and genetics. For work on adaptive immunity, he focuses on B lymphocytes and antibodies to HIV-1, while his studies of innate immunity focus on dendritic cells.
The immune system protects vertebrates from a multitude of pathogens, and two types of immune responses have evolved to accomplish this task: innate and adaptive. 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 recognize almost any antigen, as well as self-reactive receptors, which must be silenced to prevent autoimmune diseases.
The multitude of antigen receptors produced by V(D)J recombination are relatively low-affinity and must be refined by somatic hypermutation and class switch recombination to produce the high-affinity antibodies that protect against most pathogens including HIV-1. Hypermutation and selection occur in specialized micro-anatomical compartments called germinal centers. Dr. Nussenzweig’s laboratory investigates the molecular basis of hypermutation, and selection for high affinity antibody-producing cells in the germinal center.
Understanding the rules that govern hypermutation and selection is especially relevant to effective vaccine responses. Dr. Nussenzweig’s research aims to understand these processes with the goal of creating vaccines for pathogens such as HIV-1. As part of that effort the Nussenzweig laboratory has cloned highly potent human antibodies to HIV-1 that are being used in clinical studies of HIV-1 prevention and therapy.
A second area of interest is the physiological function and development of dendritic cells. Current studies focus on outlining the pathway of human dendritic cell development and differentiation.
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-antigens. By establishing tolerance to self-antigens 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 significant 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 step toward antigen-specific targeting.
New York University
The Rockefeller University
New York University School of Medicine
Internship and Residency in medicine, 1982–1985
Fellowship in infectious diseases, 1984–1985
Massachusetts General Hospital
Harvard Medical School, 1986–1989
Assistant Professor, 1990–1994
Associate Professor, 1994–1996
Director, Christopher Browne Center for Immunology and Immune
The Rockefeller University
Senior Physician, 1996–
The Rockefeller University Hospital
Assistant Investigator, 1990–1995
Associate Investigator, 1995–1999
Howard Hughes Medical Institute
Meritorious Career Award, American Association of Immunologists–Huang Foundation, 2004
Lee C. Howley Sr. Prize for Arthritis Research, 2008
National Academy of Sciences
National Academy of Medicine
American Academy of Arts and Sciences
Brazilian Academy of Sciences
Caskey, M. et al. Viremia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature 522, 487–491 (2015).
Cohn, L.B., et al HIV-1 integration landscape during latent and active infection. Cell 160, 420–432 (2015)
Gitlin, A.D. et al. Clonal selection in the germinal centre by regulated proliferation and hypermutation. Nature 509, 637–640 (2014).
Shulman, Z. et al. Dynamic signaling by T follicular helper cells during germinal center B cell selection. Science 345, 1058–1062 (2014).
Halper-Stromberg, A. et al. Broadly neutralizing antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized mice. Cell 158, 989–999 (2014).