Review
The road to the discovery of dendritic cells, a tribute to Ralph Steinman

https://doi.org/10.1016/j.cellimm.2012.01.002Get rights and content

Abstract

While it was known by the 1960s that lymphocytes mediated adaptive immunity, it was unknown how antigens stimulated lymphocytes. Between 1967 and 1973, we reported that a rare cell type in murine spleen cells took up antigen and were obligatory for T cell dependent and independent antibody responses. We referred to them as A cells or the third cell type. In 1973, Ralph Steinman and Zanvil Cohn described a rare cell type in murine spleen cells which was phagocytic but had dendrite like protrusions; they named them dendritic cells (DCs). In 1978, Steinman reported that DC were required for mixed lymphocyte reactions. From that time until recent death, Ralph Steinman pursued relentlessly in his laboratory and through collaborations around the world the role and function of DC in immunity. In passing, using a monoclonal antibody supplied by Steinman, we showed that A cells were the same as DC.

Introduction

Cellular immunology has come a long way in the last 60 plus years. In 1958, Trowell concluded his review in the International Review of Cytology: “The small lymphocyte seems a poor sort of cell, characterized by mostly negative attributes: small in size, with especially little cytoplasm, unable to multiply. Dying on the least provocation, surviving in vitro for only a few days, living in vivo for perhaps a few weeks. It must be regretfully concluded, however, that the office of this Cinderella cell is still uncertain [1]”. Soon, the situation changed mainly because technical advances made it possible to enumerate accurately lymphocyte subpopulations and to quantify the role of different kinds of lymphocytes in the production of antibodies and in the generation of helper and cytolytic lymphocytes. Although a role for non-lymphoid cell in these responses was suggested, different laboratories using different experimental models concluded that antigen either stimulated lymphocytes directly or only after being phagocytosed and presented by macrophages [2], [3], [4], [5], [6]. In the following discussion, early data from University of Chicago investigators are emphasized because their studies were concerned with the characteristics of the essential nonlymphoid cell type. At the time, other investigators focused mainly on how subcellular fractions of macrophages exposed to antigens stimulated lymphocytes [2], [3], [4], [5], [6].

Section snippets

The University of Chicago, 1967–1973

In 1966, a freshman medical student at the University of Chicago, Donald Mosier, came to our laboratory as an MD, PhD candidate proposing to determine whether macrophages (Mφ) were indeed necessary for antibody production by lymphocytes. We knew that the spleen was the site of antibody formation when antigens such as sheep red blood cells were injected intravenously [7]. Presumably the spleen contained all the cell types necessary for antibody production. If an antibody response could be

The Rockefeller Institute, 1962–1973

Beginning in 1962, Dr. Zanvil Cohn working with his colleague, Dr. James Hirsch, at the Rockefeller Institute, turned his research attention almost exclusively to the study of mononuclear phagocytes: their morphology as determined by light, phase and electron microscopy, their behavior and changing morphology in culture and their biochemistry and metabolism (reviewed in [21]). Ralph M. Steinman, MD, Harvard 1968, became a post-doctoral fellow with Cohn in 1970 after a residency at Massachusetts

Leiden, The Netherlands, 1973

By one measure the discovery of DC cells in immunity can be dated to September 1973 during a conference in Leiden on mononuclear phagocytes [23]. During the morning session, Steinman reported his work with Cohn describing a novel cell type in adherent cells obtained from mouse spleen cells. The cells were rare (<1% of all adherent cells), irregular in shape with dendritic protrusions, more mobile and less phagocytic than Mφ. The cells detached beginning after several hours. Other differences

Leiden to 1987

Steinman and his collaborators moved their research to immunology and reported that their DC stimulated B and T lymphocytes and were necessary for CTL responses of mouse and human lymphocytes [27], [28], [29], [30]. For this work, they had developed procedures for purifying DC and produced a monoclonal antibody (mAb 33D1) cytotoxic for DC [31], [32]. In 1985 we found that the mAb 33D1 supplied by Steinman eliminated the responses we were measuring including mixed lymphocyte reactions [33], [34]

1985 to the present

By the mid-1980s, the accumulating evidence from laboratories world-wide confirmed and expanded on the importance of DC in immunity. A great portion of the research on DC from 1985 to the present was by Ralph Steinman and his collaborators or was stimulated directly by their work. The rapidity and extent of advance is very nicely illustrated in an excellent review on the immunobiology of DC in the year 2000 [39] in which 281 references of original research articles are cited: seven from 1987 to

Conclusion

The key observations establishing the obligatory requirement for the cells, now called DC, in humoral and cellular immunity were made more than 40 years ago. The original reports were widely disputed or disregarded for diverse reasons, but by the mid-1980s, the importance of DC began to be widely appreciated, reflected by the almost exponential yearly increase in research articles on DC from 1987 to the present. The diversity of DC types, distribution, the many functions, and the potential use

Disclosures

The authors have no financial conflict of interest.

References (45)

  • O.A. Trowell

    The lymphocyte

    Int. Rev. Cytol.

    (1958)
  • M. Fishman

    Antibody formation in tissue culture

    Nature

    (1959)
  • B.A. Askonas et al.

    Immunogenicity of antigen-containing ribonucleic acid preparations from macrophages

    Nature

    (1965)
  • M. Fishman

    Antibody formation in vitro

    J. Exp. Med.

    (1961)
  • M. Fishman et al.

    Antibody formation initiated in vitro. II. Antibody synthesis in x-irradiated recipients of diffusion chambers containing nucleic acid derived from macrophages incubated with antigen

    J. Exp. Med.

    (1963)
  • R. Gallily et al.

    The role of macrophages in the induction of antibody in x-irradiated animals

    Immunology

    (1967)
  • D.A. Rowley

    The effect of splenectomy on the formation of circulating antibody in the adult male albino rat

    J. Immunol.

    (1950)
  • R.I. Mishell et al.

    Immunization of normal mouse spleen cell suspensions in vitro

    Science

    (1966)
  • N.K. Jerne et al.

    Plaque formation in agar by single antibody-producing cells

    Science

    (1963)
  • D.A. Rowley et al.

    Homeostasis of antibody formation in the adult rat

    J. Exp. Med.

    (1964)
  • D.E. Mosier

    A requirement for two cell types for antibody formation in vitro

    Science

    (1967)
  • L.W. Coppleson et al.

    A quantitative study of the chorioallantoic membrane reaction in the chick embryo

    Proc. R. Soc. Lond. B Biol. Sci.

    (1966)
  • D.E. Mosier et al.

    A three-cell interaction required for the induction of the primary immune response in vitro

    Proc. Natl. Acad. Sci. USA

    (1968)
  • D.E. Mosier et al.

    Cellular deficit in thymectomized mice

    Nature

    (1970)
  • R.H. Waterston

    Antigen competition: a paradox

    Science

    (1970)
  • H. Cosenza et al.

    The third cell type required for the immune response of spleen cells in vitro

    J. Immunol.

    (1971)
  • H. Cosenza et al.

    Cell interactions in antibody formation in vitro. I. Role of the third cell in the in vitro response of spleen cells to erythrocyte antigens

    J. Immunol.

    (1972)
  • L.D. Leserman et al.

    Cell interactions in antibody formation in vitro. II. The interaction of the third cell and antigen

    J. Immunol.

    (1972)
  • A. Weiss et al.

    Macrophages suppress CTL generation in rat mixed leukocyte cultures

    J. Immunol.

    (1977)
  • A. Weiss et al.

    Suppression of the plaque-forming cell response by macrophages present in the normal rat spleen

    J. Immunol.

    (1978)
  • R.M. Steinman et al.

    Zanvil Alexander Cohn 1926–1993

    J. Exp. Med.

    (1994)
  • R.M. Steinman et al.

    The interaction of soluble horseradish peroxidase with mouse peritoneal macrophages in vitro

    J. Cell Biol.

    (1972)
  • Cited by (32)

    • Automated cell cluster analysis provides insight into multi-cell-type interactions between immune cells and their targets

      2020, Experimental Cell Research
      Citation Excerpt :

      Specific clusters are also formed by the numerous different cell types present in dissociated mouse spleens in vitro, which can re-aggregate into functional groups. This functional re-aggregation provided the experimental basis for the discovery of the antigen-presenting cell (APC), referred to as the “A cell” and eventually named the dendritic cell (DC) [2]. These cells play a central role in the induction of immune responses of lymphocytes in vitro [3], and are involved in cell clusters and interactions among multiple different types, i.e., with CD4+ and CD8+ T lymphocytes.

    • Silencing SOCS1 in dendritic cells promote survival of mice with systemic Candida albicans infection via inducing Th1-cell differentiation

      2018, Immunology Letters
      Citation Excerpt :

      The most pivotal cells in the induction of immune responses are dendritic cells (DCs) [6]. DCs are the most potential antigen-presenting cells in immune system, whose maturation and functional state determine the outcome of immune response [7]. Mature DCs prime naïve CD4+ T cells into Th1, Th2, and Th17 in response to pathogens; however, immature DCs can induce anergy of naïve CD4+ T cells and suppress immune response [8].

    View all citing articles on Scopus
    View full text