Michel C. Nussenzweig, M.D., Ph.D.
Sherman Fairchild Professor; Investigator, HHMI
Laboratory of Molecular Immunology
E-mail: nussen@rockefeller.edu
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 systems that have evolved to accomplish
this task: innate and adaptive responses. 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 enables the production of a very large number of unique receptors that are able to recognize almost any antigen, but also produces self-reactive receptors, which must be silenced to prevent autoimmune diseases.
A series of checkpoints have 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 are dependent 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, these are relatively low affinity receptors that must be refined by somatic hypermutation and class switch recombination to produce the high affinity antibodies that are protective against most pathogens. Dr. Nussenzweig’s laboratory 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 his 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 used a monoclonal antibody to a dendritic cell-restricted endocytic receptor, DEC-205. This route of antigen delivery proved to be 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 re-challenge with antigen. Co-injection 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 significant implications for development of vaccines and therapies for autoimmunity.
CAREER
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 Steinman, and his M.D. in 1982
from 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 came to Rockefeller in 1990 as assistant
professor. He was named associate professor
in 1994 and professor and senior physician
in 1996. In 2000, Dr. Nussenzweig was named
Sherman Fairchild Professor.
Dr. Nussenzweig received the American
Association of Immunologists Huang Foundation
Meritorious Career Award in 2004 and
the Solomon A. Berson Award for Basic
Science in 2003. He is a member of the American
Academy of Arts and Sciences and the
American Society of Clinical Investigators. He
is also an investigator at the Howard Hughes
Medical Institute.
