This month’s selected paper for Pillars of Immunology is the 1973 description by Ralph M. Steinman and Zanvil A. Cohn of a novel cell type, found in peripheral lymphoid organs of mice, that the authors named “dendritic cells” (DC) (1). This paper was the first of a series of five to be printed in The Journal of Experimental Medicine from 1973 to 1979 (1, 2, 3, 4, 5). The strange looking and rare spleen DC now are well known to be a major player in both innate resistance and adaptive immunity by regulating the response of T, B, and NK lymphocytes; by having specialized and efficient mechanisms of Ag processing and presentation; and by being very efficient and early producers of proinflammatory cytokines and IFNs upon exposure to pathogens. We understand now that DC are very heterogeneous; are composed of different subsets; and, depending on the subset or on the stage of maturation/activation of each subset, can mediate different immunological functions, from induction of tolerance to full activation of the innate and adaptive defensive responses. DC have been defined as the sentinels of the immune system and the most potent “professional” Ag-presenting cells, but even these encompassing term, fail to completely define the complex functions of DC.
The interest in DC research has not been limited to studies of basic immunology. The possibility of harnessing the immuno-stimulating potential of DC for clinical application has generated great interest. Preclinical models or clinical trials have been designed either to use adoptive transfer of Ag-pulsed DC or to target them in vivo. Thus, the elegant but relatively simple original paper has been followed in the years since by an explosion of published papers investigating different basic or translational aspects of DC biology, reaching >6,000 papers annually in the last couple of years (see Fig. 1). Ralph Steinman has not only supported the study of DC biology in its first uneasy steps, but has continued to champion the role of this cell type in immunity. It is difficult to find any major advance in this field in which he has not been directly involved.
When DC first were defined, there was much interest in identifying the cells responsible for follicular retention of Ags in the lymph nodes. It had been shown that Ag-Ab complexes were retained on the surface of dendritic follicular reticular cells (6, 7). Also, skin biologists and dermatologists were busy studying another cell type with dendritic morphology, the Langerhans cells of the epidermis, and its relationship with allergy (8). The relationship, or lack of it, between splenic DCs and Langerhans cells became a major subject of study of the Steinman group and many other investigators. However, little was understood at that time about the mechanisms of Ag presentation to T cells. Although class II MHC molecules were known to be involved in the stimulation of mixed leukocyte culture, and class I MHC were known to be important for graft rejection, it was not until 1974 that Doherty and Zinkernagel (9) published their paper on MHC restriction of cytotoxic T cell responses. The exact role of MHC in Ag presentation was mysterious and the source of stimulating intellectual discussions among immunologists. At that time and for a few more years, macrophages, with their ability to internalize pathogens and Ags and to express both class I and class II MHC, were thought likely to be the most potent and early Ag-presenting cells during an infection (10). When Steinman and Cohn identified and characterized in vitro the DC in spleen and lymph nodes, they rejected the old nomenclature of reticular or reticulum cells, as they felt that the term was “losing its usefulness as a functional entity” (2). They showed that DC were distinct from macrophages and collagen-producing fibroblasts and had a rapid turnover in the spleen. The authors studied the follicular DCs responsible for Ag retention and postulated that the cells might in some way be related to DC characterized in vitro but not fully identifiable with them (11, 12). Surprisingly, the method of identification and purification of DC used at that time did not allow Steinman and Cohn to identify DC in the thymus (1), even though it is known now that DC are present in the thymus (although at ∼5-fold lower frequency than in the spleen) and with a different representation of the various subsets (13). Finally, in 1978–1980, Steinman and collaborators showed that DC were much more potent stimulators of mixed leukocyte culture and cytotoxic lymphocyte generation than any other spleen cell subset, including macrophages. They also recognized the primary role of DC as Ag presenting cells (14, 15). Future studies fully confirmed their conclusions and showed that DC have particular and unique mechanisms of Ag uptake, processing, and presentation on class I and class II MHC that make them efficient Ag presenting cells. This joined with unique characteristics of in vivo migration and immuno-regulatory cytokine production, accounts for their definitions as professional Ag presenting cells and sentinels of the immune system. In 1980, at a meeting discussion (16), Emil Unanue prophetically stated: “A given immune function is seldom ascribed to just a single element…. You do not have one chemotactic factor but three chemotactic factors…. I would not be surprised and I accept that there are several Ag presenting cells…. I am not saying that the Ag presenting function is exclusively on the macrophage.” We know now that the identified chemotactic factors and chemokines are too many for anybody to recollect all, and also that DC have now been subdivided into several different subsets. The different DC subsets and the other Ag presenting cells, such as macrophages and B lymphocytes, all play a significant and complex role in the development of the immune system and in the response to pathogens, but the unique functions of DC are now firmly recognized and the molecular mechanisms of these functions have been largely identified.
It was not until 1980 that Steinman’s group identified the human DC as a minor component of PBMC (17) and opened the way for studies of these cells as potent inducers of immunity against infections and tumors. However, both in the mouse and in humans, it remained very difficult to purify large numbers of this rare cell type, and the progress in their functional and biochemical characterization was painstakingly slow. Important advances included the discovery that granulocyte-macrophage CSF (GM-CSF) was a major factor for the growth and differentiation of DC precursors and that GM-CSF, alone or in combination with TNF, could be used for the generation of DC from mouse or human hemopoietic precursor cells (18, 19). Then it was shown that human monocytes cultured in the presence of GM-CSF and IL-4 could be induced to differentiate into cells with the characteristics and functions of DC (20, 21). The ability to generate in culture a large number of DC had a great impact on the ability of different groups to study both mouse and human DC biology and to harness their immuno-stimulatory abilities for translational studies and, finally, many clinical trials of tumor therapy. The modest “novel cell type” of 1973 thus has grown into one of the brightest stars of the immunology firmament.
Abbreviation used in this paper: DC, dendritic cell.