Download Ralph Steinman and dendritic cells

Immunology and Cell Biology (2012) 90, 1–2
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OBITUARY
Ralph Steinman and dendritic cells
Immunology and Cell Biology (2012) 90, 1–2; doi:10.1038/icb.2011.91; published online 25 October 2011
O
n the morning of 3 October, we were confronted with news
evoking totally contradictory emotions. We celebrated that
Ralph Steinman, along with Bruce Beutler and Jules Hoffman, had
been awarded the 2011 Nobel Prize for Physiology and Medicine. At
the same time we heard that Ralph had finally lost his 4-year battle
against pancreatic cancer, sadly before he knew of the award. The
entire Australasian Immunology Community and especially those who
work on dendritic cells (DCs) extend their deepest sympathies to
Ralph’s family, friends and work colleagues. Immunology has lost one
of its finest scientists and inspirational leaders.
Ralph Steinman has for many years rightly been considered the
father of DC research. He was a Canadian, with a science degree from
McGill, a medical degree from Harvard and further medical training
from Massachusetts General Hospital. His extensive research on DCs
was conducted during his long career at the Rockefeller University in
New York, beginning as a post-doctoral fellow and progressing to be
the Henry G Kunkel Professor and Editor of the Journal of Experimental Medicine. The modern concept of DCs as conductors of the
immune orchestra1 owes much to Steinman’s work and leadership.
We now consider DCs to be the crucial antigen-presenting cells
that mediate between the innate and adaptive immune systems. DCs
collect and process antigens for presentation on MHC molecules to
T lymphocytes. DCs also sense the environment via innate receptors for inflammatory mediators, for damaged cells or for microbial
products, and then direct an appropriate adaptive immune response
from the T cells reactive with the presented antigen. In their quiescent
state, the presentation of self-antigens by the DCs serves to maintain
self-tolerance. Following pathogen invasion, the DCs are activated by
the signals they receive via their innate receptors. T cells reactive with
the foreign antigens presented by the DCs are then driven to an
immune response tailored to the infection. The 2011 Nobel Prize
reflects the development of this model, as Beutler and Hoffman
discovered receptors that recognise microbial products and activate
the innate immune system, including DCs.
The current acceptance of this model belies the struggle in Steinman’s path to assigning DCs as the central cells. In 1973, Steinman,
working with Zanvil Cohn, identified cells with a distinctive dendritic
morphology as a rare component of a spleen cell suspension.2 The
‘veiled’ cells noted by others in lymph were, in retrospect, also DCs.
However, few at that time were impressed by the particular morphology described in such reports, as other cells, including macrophages,
can acquire a dendritic form. However, Steinman considered
them a distinct cell type. He would need great courage of his convictions in this pursuit, as it took 10 years before the specialised
antigen-presenting role of DCs was clearly established. The crucial
finding was that almost all of the antigen-presenting, T-cell-stimulating function in mixed leucocyte reactions could be attributed to the
small number of DCs present.3 Steinman and his research team then
The image of Ralph Steinman was taken at the Australasian Society for
Immunology 2010 Conference in Perth, Australia, where he was an invited
speaker. The image is provided by and used with the permission of Alan
Baxter, Comparative Genomics Centre, James Cook University, Townsville,
Queensland 4811, Australia.
led the rapidly expanding DC field: improving DC isolation procedures, developing monoclonal antibodies recognising DC surface
components, analysing DC populations by flow cytometry and clarifying DC antigen-processing functions. Particularly important was his
collaboration with scientists with a dermatology background, showing
that epidermal Langerhans cells were a form of DC.4 Langerhans cells
then served as the classic model of DCs as sentinels, collecting antigens
in their immature state in the periphery, then migrating to lymph
nodes as mature DCs to present the antigens to T cells.
In addition to all his contributions to basic DC biology, Ralph
Steinman was a passionate advocate for applying this new knowledge to the human immune system. His laboratory carried out many
of the early studies on the interaction of HIV with DC during the
development of AIDS. He believed that DCs could be manipulated
for clinical benefit, either suppressing immune responses to reduce
or prevent autoimmune pathology, or enhancing immune responses
to improve vaccines against infectious disease or against tumours.5
Much publicity has now been given to the fact that Ralph himself
tried a form of DC immunotherapy for his own pancreatic cancer.
More publicity should be given to the approach he was developing of
targeting antigens directly to DCs in situ, by injecting antigens coupled
to antibodies against DC surface molecules. The series of papers on
targeting DEC-205, from Steinman’s laboratory in collaboration with
the laboratory of Michel Nussenzweig, attest to the promise of this
new strategy, soon to be in clinical trials.
Obituary
2
Ralph Steinman’s leadership of the DC research community was
never more apparent than at the series of biennial International DC
Symposia. His opening presentations and summing-up talks were
clear, insightful and inspirational. His enthusiasm for the science was
neither diminished by doubting criticism from others nor even by his
severe illness. Some have observed that for Ralph the science and the
people doing it were inextricably linked. His introduction of a speaker
always involved some personal background, often with carefully
researched slides. Certainly, most in the DC field believed that the
first and essential step to introducing a new concept or finding was a
quiet talk with Ralph. Probably everyone in the DC field has submitted
a paper believing (rightly or not) that the key to the gate of acceptance
or rejection was held by Ralph Steinman. So it may be worth noting
the fate of a recent manuscript by Shklovskaya/Fazekas de St Groth
averring that Langerhans cells are always tolerogenic, a view that was
opposed by many and certainly contradicted earlier results from
Steinman’s laboratory. Despite this, Ralph Steinman guided the manuscript through review such that one of his last actions was
to authorise acceptance in Proceedings of the National Academy of
Science, USA.
Immunology and Cell Biology
Ralph Steinman’s legacy is a thriving research field. Much of the
detailed knowledge of DC biology needed for clinical applications is
now available. We should follow through with the same dedication,
resilience, enthusiasm and scientific solidity that characterised Ralph’s
own remarkable research career.
Ken Shortman
Walter and Eliza Hall Institute of Medical Research,
1G Royal Parade, Melbourne, Victoria 3052, Australia
E-mail: [email protected]
1 Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998;
392: 245–252.
2 Steinman RM, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs
of mice. J Exp Med 1973; 137: 1142–1162.
3 Steinman RM, Gutchinov B, Witmer MD, Nussenzweig MC. Dendritic cells are the
principal stimulators of the primary mixed leucocyte reaction in mice. J Exp Med 1983;
157: 613–627.
4 Schuler G, Steinman RM. Murine epidermal Langerhans cells mature into potent
allostimulatory dendritic cells in vitro. J Exp Med 1985; 161: 526–546.
5 Steinman RM, Banchereau J. Taking dendritic cells into medicine. Nature 2007; 449:
419–426.