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Father of Dendritic Cells and Nobel Laureate

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Ralph M. Steinman has received many awards and honors during the past few years, indicating that his discovery of dendritic cells (DCs) and their central role in immunology and medicine had finally been broadly acknowledged. Tragically, he passed away only a few days before the Nobel Committee had announced that he was to be one of the recipients of the Nobel Prize in Physiology or Medicine 2011.

Ralph Steinman was born in Montreal in 1943. After a residency in internal medicine at the Massachusetts General Hospital in Boston, he joined the Rockefeller University as a postdoctoral fellow and stayed at this unique institution ever since. Already in 1973 he identified, together with Zanvil Cohn, a world leader in macrophage research and innate immunity at that time, a new cell type in peripheral lymphoid organs of mice on the basis of their unusual dendritic morphology and motility 1, and also based on their functional differences from macrophages and lymphocytes 2. This was followed by Steinman's discovery of many distinctive features of both mouse and human DCs, as well as several truly fundamental concepts in immunology. Steinman learned to enrich these infrequent (∼1% in most lymphoid tissues) cells, and uncovered, as a first important function, that they were the key stimulators in the primary mixed leukocyte reaction and of transplant immunity, while antigen-bearing B cells and macrophages contributed little to immune initiation. Thus, DCs converted transplantation antigens into immunogens, i.e. making antigens capable of eliciting immunity. DCs were unusually potent, such that very few cells were required to induce immunity. These findings allowed Steinman to predict already in 1978 that “dendritic cells will prove to be a critical accessory cell required in the generation of many immune responses” 3.

Steinman observed that these few DCs gathered the antigen-reactive T cells within aggregates that could be studied directly, a microenvironment for the generation of immunity 4, 5. DCs were also identified in the blood. The need of DCs for the development of cytotoxic or killer T lymphocytes was then shown. The development of the first monoclonal antibody to selectively deplete the scarce DCs provided an independent approach to convincingly demonstrate the major role for these cells in the onset of immunity 6. A series of experiments led to the realization that immune responses developed in two stages both requiring the presentation of antigen to specific clones of lymphocytes: an afferent limb, in which DCs served as critical accessories to initiate T-cell mediated immunity from infrequent quiescent clones, both expanding and differentiating into helper and killer functions; and an efferent limb, when the recently activated and expanded T cells encountered antigens processed and presented by other cells including B cells, macrophages and other cellular targets.

The discovery of the maturation of DCs was another important step forward 7 as it unraveled some of the functions of antigen presenting cells showing that the cells had two key attributes that could be segregated in time: antigen capture by immature DCs and accessory or co-stimulatory roles by mature forms 8. DC maturation, and not only antigen presentation, was required for different types of immune responses and proved to be a key control point of cellular immunity. Importantly, Steinman also showed in seminal studies that antigen-presenting DCs if not matured are not inactive but tolerogenic 9. Steinman has emphasized that these tolerizing functions solve an apparent dilemma. The dilemma is that when infections strike, DCs inevitably capture harmless self and environmental antigens as well as microbial proteins. DCs help to solve the potential autoimmune-inducing danger of self antigens by having several mechanisms to dampen immune responses to harmless antigens that are captured in the steady state, prior to infection.

Steinman's group then proceeded to apply antigens to maturing DCs ex vivo and to reinject the cells into mice. The DCs were initially isolated from spleen, pulsed with protein antigens and subsequently administered to naive mice. As a result, T cells were specifically and directly immunized to the antigens presented on the MHC products of the DCs 10. Showing that DCs could initiate immunity in vivo led to their designation as “nature's adjuvants”. The findings also suggested that ex vivo loaded DCs could be used to vaccinate patients if only DCs were easily available in higher numbers. The finding that GM-CSF could be used to grow large numbers of DCs from mouse blood 11 and then from bone marrow as well as from human blood made DCs more accessible to scientists worldwide, triggering a major expansion in research and enormously accelerating the pace of discovery.

Steinman and associates also demonstrated that DCs generated from precursors are immunogenic in vivo in the presence of antigens, including microbial antigens in mice, model antigens in human volunteers 12 and tumor antigens in cancer patients 13. Along with colleagues, Steinman also learned to target antigens to DCs in situ by introducing peptides and proteins with antibodies that recognize an endocytic receptor, DEC-205, expressed by DCs within lymphoid tissues 14. When antigens are targeted to DCs in vivo, without added stimuli for their maturation, antigen processing and recognition by T cells takes place, but the outcome is tolerance. In contrast, delivery of an appropriate maturation stimulus together with the targeted antigen leads to immunity rather than tolerance. Other such receptors were identified and upon targeting gave rise to distinctive immune responses, indicating that it should be possible to induce or dampen distinct immune responses with precision to treat diseases. In fact Steinman's group has been systematically exploring the DEC-205 approach to induce CD4+ and CD8+ T-cell immunity to HIV antigens over the past years in mice and non-human primates, and a clinical trial is now ongoing. This strategy may change the field of protein vaccines allowing the reliable induction of CD4+ as well as CD8+ T-cell immunity to multiple epitopes by a non-live vaccine.

Ralph Steinman was a genuine physician–scientist always emphasizing that we have to bring new knowledge forward to the clinic to help patients. He was interested in vaccines for a long time and tirelessly emphasized the need to consider and exploit the biology of DCs for vaccines optimized to induce T-cell immunity. Furthermore, Steinman's pioneering research has stood the test of time. It has stimulated both immunological and medical research worldwide. Before DCs were identified and their basic role uncovered, we could not really understand how T-cell mediated immunity worked and how the immune orchestra was conducted.

The insights into DC biology are now crucial to understand and fight diseases, notably by designing better vaccines. Thus, it is no surprise that virtually every issue of most contemporary immunology journals contain articles on DCs; however, at least for the first 15 years after the initial reports of DCs, few immunologists studied these cells and many questioned their relevance or existence. In retrospect, this seems strange because if one reads the initial reports again they appear crystal clear so that the non-acceptance of the novel concept appears somewhat irrational today. At that time, however, the idea of a new and scarce hematopoietic lineage, which Steinman claimed to be “nature's adjuvant” for the initiation of antigen-specific immune responses, was totally against the mainstream view that macrophages were the logical cells to perform this function. Fortunately, Ralph Steinman was not the person to get discouraged, and was stubborn and brave enough to continue working on DCs.

Ralph Steinman was an enthusiastic teacher and mentor to many colleagues, and supportive to everyone genuinely interested in science. He was a brilliant scientist, and extremely smart. Ralph also very deeply impressed me as a caring and understanding human being, and because his family was so important to him. Ralph Steinman's legacy is immortal and will inspire generations of scientists. His scholars and friends will miss this unforgettable man not only as a scientist but also as a human being. I can only hope that this is some solace to his beloved family.

Gerold Schuler

Department of Dermatology, University Hospital Erlangen, Germany e-mail: gerold.schuler@uk-erlangen.de

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