It is probably difficult for the younger readers of this journal to recall a time when molecularly defined cytokines were unavailable, their signaling mechanisms unknown, and their roles in regulation of cell proliferation and differentiation unrecognized. William E. Paul, M.D., who died on September 18, 2015 at age 79, was a pioneer who led in the transition of cytokine biology from the study of uncharacterized supernatant factors to quantitative examination of the action of cloned entities and from phenomenological observations of bulk activities to molecular exposition of intracellular signaling pathways. Although his specific research focus was on the cytokine IL-4, he contributed in many additional and crucial ways to the development of modern immunobiology. Bill’s research helped elucidate the mechanisms controlling Ig production and class determination. He played a significant role in the early development of our understanding of T cell Ag recognition and composed highly influential theoretical papers on immune regulation. Bill was a mentor to many young scientists now famous in their own right, and he was an exemplary citizen who served on editorial boards, advisory panels, deliberative bodies, and scientific professional organizations, including service as President of The American Association of Immunologists (AAI) from 1986 to 1987.

William E. Paul

Photo courtesy of Ronald N. Germain, M.D., Ph.D.

William E. Paul

Photo courtesy of Ronald N. Germain, M.D., Ph.D.

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Bill’s service as AAI president was the culmination of his tenure on the AAI Council, which commenced in 1981. An AAI member since 1967, he also served on many AAI committees including the Program Committee (1970–1972, 1977–1980, and 1980–1981, as cochair), the Nominating Committee (1973–1974, as chair, and 1999–2000), the Committee for Travel Awards to the Third International Congress (1974–1977), the Finance Committee (1982–1984 and 1990–1992), and the Awards Committee (1993–1996). He also served as an Associate Editor (1971–1975), Section Editor (1975–1978), and on the Editorial Board (now the Publications Committee) (1979–1984) for The Journal of Immunology. [Bill’s curriculum vitae included over 130 articles published in the journal; the most recent was published in the February 1, 2015 issue (1).] Bill represented AAI in national and international organizations, including the Federation of American Societies for Experimental Biology Board (1985–1988) and the International Union of Immunological Societies General Assembly (1986–1987).

In 2002, Bill was a recipient of the AAI Lifetime Achievement Award, the highest honor bestowed by the AAI Council, in recognition of his scientific achievement and contributions to AAI and fellow immunologists. In 2014, he received the AAI Excellence in Mentoring Award, recognizing his dedication to, and significant influence on, the professional development and career achievements of trainees.

Bill grew up in New York City. His father, born in the Ukraine, had an auto body shop, and his mother, of Polish descent, came from a family with several scientists. For college (Brooklyn College) and medical school (State University of New York College of Medicine), Bill stayed in the New York City area, and he always made a point of noting the high quality of the education he received at these public institutions.

His first research experience came in the summers after his first and second years of medical school when he studied growth hormone production in the rat pituitary under the tutelage of George Talbert. This was not only the period in which Bill began his lifelong dedication to scientific research, but also when he wed the true love of his life, Marilyn Heller.

Bill did his internship and residency at Massachusetts Memorial Hospitals in Boston. There he continued his research activities using immunoelectron microscopy to study amyloid fibril. This work resulted in his first scientific publication, which appeared in the journal Nature (2).

In 1962, Bill first came to the National Institutes of Health (NIH) as a clinical fellow in the Endocrinology Branch of the National Cancer Institute. He took great satisfaction from his participation in the successful treatment of women with choriocarcinoma using a methotrexate protocol recently developed by R. Hertz and M.C. Lai. Beyond this clinical activity, Bill continued his research studies at the bench, working with W. Odell, J. Wilber, and others to develop the first radioimmunoassay for thyroid stimulating hormone (3). But as rewarding as these activities were, they did not satisfy Bill, who felt that he needed further training to be fully successful in a career in research. Further, he had already developed an itch for immunology. In his autobiographical essay in the Annual Review of Immunology, Bill described this epiphany:

“I still recall my first attraction to immunology. Somehow, I came into possession of a slender volume of essays by Michael Heidelberger, the father of quantitative immunochemistry, describing the remarkable specificity of antibodies and his vision of the chemical forces underlying this specificity. I recall that I started reading this on a trolley car in Brooklyn, during my college days, and I was smitten.” (4)

With this strong desire to pursue research in immunology foremost in his mind, Bill sought input about how to proceed from Boston immunologists Byron Waksman and Sidney Lefkowitz. He received clear advice from both: go to New York City to study with either Henry Kunkel or Baruj Benacerraf. Kunkel only had a Ph.D. opening, which didn’t suit Bill given his growing family responsibilities, and so it was that Bill wound up in the laboratory of Benacerraf at New York University in 1964. There Bill participated in the remarkable studies that uncovered the genetic basis for immune responses (for which Benacerraf was awarded the 1980 Nobel Prize in Physiology or Medicine), helping to design and employ assays for Ab specificity that were among the first to show the distinct recognition proclivities of what later were determined to be B and T lymphocytes (57).

Remarkably, New York University found neither Bill nor Baruj suitable for promotion to positions each saw as essential to the next phase of their careers, Bill as an instructor in medicine and Baruj as the chair of a revamped Department of Anatomy. The result was Baruj’s departure to the NIH to become Chief of the Laboratory of Immunology (LI) in the National Institute of Allergy and Infectious Diseases (NIAID). Bill was asked to join him in this move, and in 1968, Bill returned to the NIH and to the 11th floor of Building 10, which remained his scientific home until his death.

Only two years after arriving at NIH, Benacerraf accepted the chair of Pathology at Harvard Medical School. With Baruj’s support, Bill became the next Chief of the LI, rising to that position in 1970 and leading the laboratory for the next 45 years. During that period, he helped make the LI an internationally recognized center for immunological research, through a combination of his own outstanding research achievements and by providing a nurturing home for other investigators, myself included, that allowed the entire department to thrive. The list of postdoctoral fellows trained in the LI during Bill’s tenure is a Who’s Who of modern immunology: a highly abbreviated list starts with John Stobo, Charlie Janeway, Ron Schwartz, Kim Bottomly, and in the following decades, Mark Davis, Laurie Glimcher, Maureen Howard, Tony DeFranco, Steve Hedrick, Wayne Yokoyama, Larry Samelson, Jon Ashwell, Dan Longo, Lou Matis, Drew Pardoll, Ellen Heber-Katz, Kenji Nakanishi, Takashi Saito, Caetano Reis e Sousa, Fred Finkelman, Melissa Brown, Bob Seder, Graham Le Gros, Josh Milner, Jim McClusky, and many, many others.

Bill is best known for his discovery, with Maureen Howard, of what was initially called B cell stimulating factor or BSF-1 (8). Now known as IL-4, much of Bill’s research at NIH centered on this cytokine, the Th2 cells that made this mediator, the signals it evoked in cells, and the roles it played in host defense and pathology (9). Bill and his associates made many fundamental contributions to our understanding of cytokine biology, showing with Cliff Snapper that IL-4 and IFN-γ controlled the production of distinct Ig isotypes (10); with Melissa Brown and Marshall Plaut that mast cells and basophils made many type 2 cytokines (11, 12); and with Graham Le Gros, Zami Ben-Sasson, and Bob Seder that the polarization of CD4 T cells involved positive feedback regulation by their prototypic cytokines (13, 14). He also helped demonstrate the role of IL-2 in T effector cell development (15), the role of IL-1 in expanding memory and effector T cells (16), and the existence of monoallelic control of cytokine gene expression (17). Bill also had a strong interest in control of the T cell repertoire, especially in lymphopenic environments, and did pioneering work in this area with Booki Min (18, 19).

Space does not permit detailing all of the many other seminal findings made by Bill and his colleagues. But Bill did not limit himself to the rigorous, insightful bench research that gave rise to these discoveries. He was a man of all seasons, making enormous contributions not just to immunology, but to the larger sphere of biomedical science through his activities as an editor, a member of advisory panels, and his service as the first director of the Office of AIDS Research (OAR) at NIH, a position he held from 1994 to 1998. Bill’s textbook Fundamental Immunology, now in its seventh edition, has served generations of budding immunologists as the definitive advanced text in the field. As the founding editor of the Annual Review of Immunology, Bill had an enormous impact on the dissemination of the latest information available across the wide spectrum of subject areas in our discipline. He and his coeditors helped make this review series one of the most cited of all publications in biomedicine for much of his tenure. As the director of the OAR, Bill had tremendous influence on how research on AIDS and HIV was conducted in those critical years, and his efforts won him praise from many in the activist community who feel Bill’s efforts saved millions of lives.

After stepping down as head of the OAR, Bill did not lose his deep interest in AIDS and HIV. Two subsequent efforts are notable. First, he played a major role along with Drs. Anthony Fauci and Harold Varmus in convincing both President Clinton and Congress to support development of the Vaccine Research Center at NIH, a research enterprise that has had substantial impact on the continuing efforts to develop safe and effective vaccines for HIV and other infectious diseases (3). Second, with his longtime colleague Zvi Grossman, Bill blended his laboratory interest in regulation of lymphocyte homeostasis with a deep consideration of the cell dynamics that lead to immunodeficiency in HIV-infected individuals, producing a series of important papers in this area over a period of nearly two decades (2024).

Some scientists achieve recognition solely based on their research productivity, others by actions in the administrative or even political realms. Some are known from their trainees’ success, yet others for their teaching skills or for their service to the community. Much more rare is the individual who combines all of these accomplishments with a universally respected demeanor. Bill Paul was considered a true gentleman; he was unfailingly gracious to others even when credit was due him; he supported those around him rather than take personal advantage of his position and control of resources; and he pushed unflaggingly for the recognition of his colleagues’ accomplishments. His questions at seminars were always directed at getting to the heart of the matter, but were never offered in such a way as to unduly highlight what we all knew was his formidable intellect. In short, he was a unique individual, adding greatly to our understanding of an enormously complex system, teaching others both how to ask the right questions and how to develop experimental results supporting insightful and valid interpretations. He promoted the best conduct in science, helped to identify and reward those who made key contributions, and overall, elevated scientific discourse to a high level. Bill occupied a very special place in the immunological and larger biomedical spheres—a huge void is left with his passing.

This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH).

View William E. Paul's 2012 interview for The American Association of Immunologists (AAI) Oral History Project and visit his profile in the History section of the AAI site: http://www.aai.org/About/History/Notable_Members/Presidents/Paul_William.html.

1
Dewas
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,
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TSLP expression: analysis with a ZsGreen TSLP reporter mouse
.
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2
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A. S.
,
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.
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.
Relationship of gamma-globulin to the fibrils of secondary human amyloid
.
Nature
197
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193
194
.
3
Odell
W. D.
,
Wilber
J. F.
,
Paul
W. E.
.
1965
.
Radioimmunoassay of thyrotropin in human serum
.
J. Clin. Endocrinol. Metab.
25
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1179
1188
.
4
Paul
W. E.
2014
.
Endless fascination
.
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32
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5
Paul
W. E.
,
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G. W.
,
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.
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.
Studies on the effect of the carrier molecule on antihapten antibody synthesis. II. Carrier specificity of anti-2,4-dinitrophenyl-poly-l-lysine antibodies
.
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123
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6
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,
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,
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.
Specificity of cellular immune responses. Antigen concentration dependence of stimulation of DNA synthesis in vitro by specifically sensitized cells, as an expression of the binding characteristics of cellular antibody
.
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42
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7
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W. E.
,
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,
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1970
.
Carrier function in anti-hapten immune responses. II. Specific properties of carrier cells capable of enhancing anti-hapten antibody responses
.
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8
Howard
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,
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M.
,
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,
Takatsu
K.
,
Hamaoka
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,
Paul
W. E.
.
1982
.
Identification of a T cell-derived b cell growth factor distinct from interleukin 2
.
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9
Paul
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2015
.
History of interleukin-4
.
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75
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7
.
10
Snapper
C. M.
,
Paul
W. E.
.
1987
.
Interferon-gamma and B cell stimulatory factor-1 reciprocally regulate Ig isotype production
.
Science
236
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944
947
.
11
Brown
M. A.
,
Pierce
J. H.
,
Watson
C. J.
,
Falco
J.
,
Ihle
J. N.
,
Paul
W. E.
.
1987
.
B cell stimulatory factor-1/interleukin-4 mRNA is expressed by normal and transformed mast cells
.
Cell
50
:
809
818
.
12
Plaut
M.
,
Pierce
J. H.
,
Watson
C. J.
,
Hanley-Hyde
J.
,
Nordan
R. P.
,
Paul
W. E.
.
1989
.
Mast cell lines produce lymphokines in response to cross-linkage of Fc ε RI or to calcium ionophores
.
Nature
339
:
64
67
.
13
Le Gros
G.
,
Ben-Sasson
S. Z.
,
Seder
R.
,
Finkelman
F. D.
,
Paul
W. E.
.
1990
.
Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells
.
J. Exp. Med.
172
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929
.
14
Seder
R. A.
,
Paul
W. E.
,
Davis
M. M.
,
Fazekas de St Groth
B.
.
1992
.
The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice
.
J. Exp. Med.
176
:
1091
1098
.
15
Yamane
H.
,
Zhu
J.
,
Paul
W. E.
.
2005
.
Independent roles for IL-2 and GATA-3 in stimulating naive CD4+ T cells to generate a Th2-inducing cytokine environment
.
J. Exp. Med.
202
:
793
804
.
16
Ben-Sasson
S. Z.
,
Hu-Li
J.
,
Quiel
J.
,
Cauchetaux
S.
,
Ratner
M.
,
Shapira
I.
,
Dinarello
C. A.
,
Paul
W. E.
.
2009
.
IL-1 acts directly on CD4 T cells to enhance their antigen-driven expansion and differentiation
.
Proc. Natl. Acad. Sci. USA
106
:
7119
7124
.
17
Guo
L.
,
Hu-Li
J.
,
Paul
W. E.
.
2005
.
Probabilistic regulation in TH2 cells accounts for monoallelic expression of IL-4 and IL-13
.
Immunity
23
:
89
99
.
18
Min
B.
,
McHugh
R.
,
Sempowski
G. D.
,
Mackall
C.
,
Foucras
G.
,
Paul
W. E.
.
2003
.
Neonates support lymphopenia-induced proliferation
.
Immunity
18
:
131
140
.
19
Min
B.
,
Foucras
G.
,
Meier-Schellersheim
M.
,
Paul
W. E.
.
2004
.
Spontaneous proliferation, a response of naive CD4 T cells determined by the diversity of the memory cell repertoire
.
Proc. Natl. Acad. Sci. USA
101
:
3874
3879
.
20
Grossman
Z.
,
Paul
W. E.
.
1992
.
Adaptive cellular interactions in the immune system: the tunable activation threshold and the significance of subthreshold responses
.
Proc. Natl. Acad. Sci. USA
89
:
10365
10369
.
21
Grossman
Z.
,
Paul
W. E.
.
2000
.
Self-tolerance: context dependent tuning of T cell antigen recognition
.
Semin. Immunol.
12
:
197
203, discussion 257–344
.
22
Grossman
Z.
,
Feinberg
M. B.
,
Paul
W. E.
.
1998
.
Multiple modes of cellular activation and virus transmission in HIV infection: a role for chronically and latently infected cells in sustaining viral replication
.
Proc. Natl. Acad. Sci. USA
95
:
6314
6319
.
23
Grossman
Z.
,
Meier-Schellersheim
M.
,
Paul
W. E.
,
Picker
L. J.
.
2006
.
Pathogenesis of HIV infection: what the virus spares is as important as what it destroys
.
Nat. Med.
12
:
289
295
.
24
Paul
W. E.
,
Milner
J. D.
,
Grossman
Z.
.
2013
.
Pathogen-sensing, regulatory T cells, and responsiveness-tuning collectively regulate foreign- and self-antigen mediated T-cell responses
.
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78
:
265
276
.