Heads of Laboratories
Senior Physician
Henry G. Kunkel Professor
Laboratory of Cellular Physiology and Immunology
Ralph.Steinman@rockefeller.edu
Dendritic cells, which were originally codiscovered by Dr. steinman with Zanvil A. Cohn at Rockefeller, are pivotal to the adaptive and innate branches of the immune system. Dr. steinman’s research focuses on the mechanisms employed by dendritic cells to regulate lymphocyte function in tolerance and immunity, as well as the use of dendritic cells to understand the development of immune-based diseases and the design of new therapies and vaccines.
The immune system contains a system of dendritic cells, which captures, processes and presents antigens and provides additional controls on the development of antigen-specific immunity and tolerance. Because of these functions, dendritic cells (DCs) are providing an important means to monitor and manipulate immune function in several disease states.
One set of DC functions involves the capture of protein antigens, which are then converted to peptides within either the endocytic system or the cytoplasm. The peptides bind to newly synthesized products of the major histocompatibility complex (MHC) — a region of the genome important for immunity and autoimmunity — and then exit to the cell surface for presentation to T cells. DCs express a number of distinct receptors for antigen uptake and processing. One of these receptors is the multilectin DEC-205. Following DEC-205-mediated uptake, antigens are efficiently presented on both MHC class I and II molecules.
Also under study is a new family of C-type lectins, called SIGNs, that recognize clinically important infectious agents. For example, DC-SIGN has an endocytic function but also binds and transmits HIV-1 from DCs to T lymphocytes. DC-SIGN is proving to be a valuable marker for certain macrophages and for monocyte-derived DCs.
A second set of DC functions relates to their role in the control of tolerance and immunity. In the absence of infection, DCs efficiently capture and process harmless self- and environmental antigens and induce immune silencing or tolerance. But during infection, DCs undergo an intricate differentiation process termed maturation. DCs express additional receptors that allow them to respond to microbial components and other environmental cues to become adjuvants, or catalysts, for the initiation of immu- nity. Dr. Steinman’s lab is linking the maturation of DCS in situ with the uptake and processing of antigens, using new methods to selectively target the antigens to DCs. This work results in antigen presentation on both MHC class I and II products, leading to the formation of functioning CD8+ killer and CD4+ helper T lymphocytes. The group is currently targeting microbial, self- and tumor antigens to DCs in different maturational states in the context of different diseases, including HIV-1 and autoimmune diabetes.
While DCs provide important innate and adaptive resistance mechanisms to infections, they also present self-antigens and harmless proteins from the environment, thereby actively silencing or tolerizing the immune system and defining immunological “self.” Along with the Rockefeller laboratories of Michel C. Nussenzweig and Jeffrey V. Ravetch, Dr. Steinman’s group is currently investigating active antigen-specific suppressor or regulatory T cell mechanisms that allow DCs to induce tolerance.
Dr. Steinman’s codiscovery of dendritic cells, with his collaborator Zanvil A. Cohn, and his subsequent work on this new class of immune cells have led to the characterization of DCs as important and unique accessories in the onset of several immune responses, including graft rejection, resistance to tumors, autoimmune disease and infections. His work has led to a new understanding of the control of tolerance and immunity and was the genesis for a new field of study within immunology: the role of DCs in immune regulation, their potential for discovering new vaccines and treatments of autoimmune disorders.
CAREER
Dr. Steinman received his undergraduate degree from McGill University in 1963 and his M.D. from Harvard Medical School in 1968. After an internship and residency at Massachusetts General Hospital, he joined Rockefeller in 1970 as a postdoc in the Laboratory of Cellular Physiology and Immunology. He was appointed assistant professor in 1972, associate professor in 1976 and professor in 1988. In 1995 he was named the Henry G. Kunkel Professor, and in 1998 he was appointed director of the Christopher H. Browne Center for Immunology and Immune Diseases.
Dr. Steinman was the recipient of the A.H. Heineken Prize for Medicine in 2010, the Albany Medical Center Prize in Medicine
and Biomedical Research in 2009 and the Albert Lasker Basic Medical Research Award in 2007. He received the Debrecen Prize in
Molecular Medicine in 2006, the New York City Mayor’s Award for Excellence in Science and Technology in 2004, the Novartis
Prize in Immunology in 2004 and the Gairdner Foundation International Award in 2003. He is a member of the National Academy
of Sciences and the Institute of Medicine.
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