IL-2: More Than a T Cell Growth Factor
Joost J. Oppenheim
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References
J Immunol 2007; 179:1413-1414; ;
doi: 10.4049/jimmunol.179.3.1413
http://www.jimmunol.org/content/179/3/1413
IL-2: More Than a T Cell Growth Factor
Joost J. Oppenheim1
1
Address correspondence and reprint requests to Dr. Joost J. Oppenheim, Laboratory
of Molecular Immunoregulation, Cancer Inflammation Program, National Cancer Institute, Frederick, MD 21701-1201. E-mail address: [email protected]
2
Abbreviations used in this paper: TCGF, tumor cell growth factor; BF, blastogenic
factor.
Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00
www.jimmunol.org
growth and differentiation of T cells and for use in the treatment of cancer patients.
The availability of TCGF made it possible to study cloned T
cells with a single antigenic specificity. This led to an understanding of how T cells recognize Ags and to the identification
of receptors for TCGF and Ags. It also led to the unanticipated
identification of Th1- and Th2-polarized T cell types. TCGF
has also proven to be of great benefit to virologists by providing
the necessary culture methodology that led to the discoveries of
human T cell leukemia virus type 1 and HIV-1.
The immunologists became very unhappy with the plethora
of terms used to describe endogenous lymphocyte-derived lymphoproliferative factors and proposed to use the more abstract
term of IL-2 (8). Scientists who favored TCGF resented this
apparent expropriation of their discovery by immunologists.
However, this resistance was overcome by reports that IL-2
acted on non-T cells and was also a growth factor for NK cells
(9) and B cells (10).
Since then, the multitudinous and complex activities of IL-2
have repeatedly surprised investigators. In addition to promoting the survival and growth of T cells, IL-2 terminally differentiates T cells for activation-induced cell death (11). The development of technology for inactivating the IL-2 gene led to
observations that IL-2 null mice paradoxically developed progressive lymphoid hyperplasia (12). The mice also developed
autoimmune syndromes such as hemolytic anemia and in a
conventional environment they subsequently developed autoimmune enteritis as well (13, 14). These consequences are now
understood to be based on the more recent surprising observations that IL-2 is a potent stimulator of T regulatory cells (15).
IL-2 is a necessary signal for the development, survival, and expansion of regulatory T cells that down-regulate self-reactive
lymphocyte responses, thus preventing anemia, enteritis, and
other autoimmune sequelae. Consequently, the unintended
discovery of Ruscetti, Morgan, and Gallo has led to our appreciation of T cell growth factors not only as promoters of the
survival and proliferation of immune effector and killer cells but
also as the pivotal inducers of T regulatory cells.
Acknowledgments
I am grateful to Drs. Scott Durum, Giorgio Trinchieri, and Francis Ruscetti
for their constructive discussions of this essay and to Cheryl Fogle-Lamb
for producing multiple drafts.
References
1. Morgan, D. A., F. W. Ruscetti, and R. C. Gallo. 1976. Selective in vitro growth
of T lymphocytes from normal human bone marrows. Science 193: 1007–1008.
2. Ruscetti, F. W., D. A. Morgan, and R. C. Gallo. 1977. Functional and morphologic characterization of human T cells continuously grown in vitro. J. Immunol.
119: 131–138.
3. Kasakura, S., and L. Lowenstein. 1965. A factor stimulating DNA synthesis
derived from the medium of leukocyte cultures. Nature 208: 794 –795.
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The 1976 and 1977 reports of the discovery of
T cell growth factor (TCGF)2 by Francis W.
Ruscetti, Doris A. Morgan, and Robert C. Gallo
sparked great interest in lymphocyte growth factors (1, 2). Although there were a number of prior reports of the
detection of factors mitogenic for lymphocytes, this discovery,
featured in Pillars of Immunology (2), made it possible to grow
and expand normal lymphocytes long term using TCGF. A
blastogenic factor (BF) capable of inducing lymphocyte mitogenesis was first detected by Kasakura and Lowenstein in the
supernatants of antigen and alloantigen-stimulated leukocyte
cultures in 1965 (3). Also in 1965 Gordon and McLean demonstrated that in vitro generation of BF in response to lymphoproliferative mitogens could be inhibited by puromycin or
5-fluorouracil, suggesting that BF was lymphocyte derived (4).
Dumonde et al. (1969) identified lymphocytes as the source of
these mitogenic factors and termed them “lymphokines” (5).
Several years later, Gery et al. reported that macrophages also
produced a “lymphocyte-activating factor” that could only support short-term growth of thymocytes and lymphocytes (6).
Chen and DiSabato discussed a number of studies investigating
short-term thymocyte-stimulating factor (7).
Ruscetti et al. were apparently unaware of these immunological laboratory efforts. Robert Gallo was aiming to identify a
means of growing myeloid cell lines long term to discover and
culture human retroviruses. They therefore obtained human
bone marrow cells as a source of myeloid precursors and cultured them with repeated additions of supernatant of PHAstimulated human blood lymphocytes (1, 2). To their surprise,
rather than the usual EBV-positive B lymphocytes, this yielded
a long-term growth of T lymphocytes that could be maintained
and expanded for 9 months only by the repeated addition
of TCGF.
Nevertheless, Bob Gallo was initially very disappointed that
this approach yielded only the “wrong” cell for the purpose of
cultivating human viruses. Despite a variety of attempts, bone
marrow-derived granulocytes and myeloid cells died during the
first week of culture, leaving only the E-rosette-forming mononuclear lymphocytes (i.e., T cells) capable of responding to
TCGF. This led them to report TCGF as a factor capable of
generating normal T cells in large quantities. As predicted in
their report, these “immortalized” normal T cells have provided
an excellent tool for molecular immunological studies of the
1414
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in vitro. Nature 208: 795–796.
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W. T. Howson. 1969. Lymphokines: non-antibody mediators of cellular immunity generated by lymphocyte activation. Nature 224: 38 – 42.
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mitogens. II. The cellular source of potentiating mediators. J. Exp. Med. 136:
143–155.
7. Chen, D. M., and G. DiSabato. 1976. Further studies on the thymocyte stimulating factor. Cell. Immunol. 22: 211–224.
8. Mizel, S. B., and J. J. Farrar. 1970. Revised nomenclature for antigen non-specific
T cell proliferation and helper factors. Cell. Immunol. 48: 433– 436.
9. Henney, C. S., K. Kuribayashi, D. E. Kern, and S. Gillis. 1981. Interleukin-2
augments natural killer cell activity. Nature 291: 335–338.
10. Zubler, R. M., Lowenthal, J. W., Erard, F., N. Hashimoto R. Devos, and
H. R. MacDonald. 1984. Activated B cells express receptors for and proliferate
in response to pure IL-2. J. Exp. Med. 160: 1170 –1183.
PILLARS OF IMMUNOLOGY
11. Lenardo, M. J. 1991. Interleukin-2 programs mouse ␣ ␤ T lymphocytes for apoptosis. Nature 353: 858 – 861.
12. Schorle, H., T. Holtschke, T. Hunig, A. Schimpl, and I. Horak. 1991. Development and function of T cells in mice rendered interleukin-2 deficient by gene
targeting. Nature 352: 621– 624.
13. Sadlack, B., H. Merz, H. Schorle, A. Schimpl, A. C. Feller, and I. Horak. 1993.
Ulcerative colitis-like disease in mice with disrupted interleukin-2 gene. Cell 75:
253–261.
14. Sadlack, B., J. Lohler, H. Schorle, G., Klebb, H. Haber, E. Sickel, R. J. Noelle,
and I. Horak. 1995. Generalized autoimmune disease in interleukin-2-deficient
mice is triggered by an uncontrolled activation and proliferation of CD4⫹ T cells.
Eur. J. Immunol. 25: 3053–3059.
15. Almeida, A. R. M., N. Legrand, M. Papiernik, and A. A. Freitas. 2002. Homeostasis of peripheral CD4⫹ T cells: IL-2R␣ and IL-2 shape a population of
regulatory cells that controls CD4⫹ T cell numbers. J. Immunol. 169:
4850 – 4860.
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