Morgan, D. A., Ruscetti, F. W. & Gallo, R.
Selective in vitro growth of T lymphocytes from normal human bone marrows. Science
193, 1007–1008 (1976).
Smith, K. A.
Interleukin-2: inception, impact, and implications. Science
240, 1169–1176 (1988).
Malek, T. R.
The biology of interleukin-2. Annu. Rev. Immunol.
26, 453–479 (2008).
Setoguchi, R., Hori, S., Takahashi, T. & Sakaguchi, S.
Homeostatic maintenance of natural Foxp3+ CD25+ CD4+ regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J. Exp. Med.
201, 723–735 (2005).
et al. Inducible IL-2 production by dendritic cells revealed by global gene expression analysis. Nature Immunol.
2, 882–888 (2001).
Hershko, A. Y.
et al. Mast cell interleukin-2 production contributes to suppression of chronic allergic dermatitis. Immunity
35, 562–571 (2011).
Martins, G. A., Cimmino, L., Liao, J., Magnusdottir, E. & Calame, K.
Blimp-1 directly represses Il2 and the Il2 activator Fos, attenuating T cell proliferation and survival. J. Exp. Med.
205, 1959–1965 (2008).
Kallies, A., Xin, A., Belz, G. T. & Nutt, S. L.
Blimp-1 transcription factor is required for the differentiation of effector CD8+ T cells and memory responses. Immunity
31, 283–295 (2009).
Rutishauser, R. L.
et al. Transcriptional repressor Blimp-1 promotes CD8+ T cell terminal differentiation and represses the acquisition of central memory T cell properties. Immunity
31, 296–308 (2009).
et al. A role for the transcriptional repressor Blimp-1 in CD8+ T cell exhaustion during chronic viral infection. Immunity
31, 309–320 (2009).
Lenardo, M. J.
Interleukin-2 programs mouse αβ T lymphocytes for apoptosis. Nature
353, 858–861 (1991).
Van Parijs, L. & Abbas, A. K.
Homeostasis and self-tolerance in the immune system: turning lymphocytes off. Science
280, 243–248 (1998).
Taniguchi, T. & Minami, Y.
The IL-2/IL-2 receptor system: a current overview. Cell
73, 5–8 (1993).
Boyman, O., Kovar, M., Rubinstein, M. P., Surh, C. D. & Sprent, J.
Selective stimulation of T cell subsets with antibody–cytokine immune complexes. Science
311, 1924–1927 (2006).
Wang, X., Rickert, M. & Garcia, K. C.
Structure of the quaternary complex of interleukin-2 with its α, β, and γc receptors. Science
310, 1159–1163 (2005).
Waldmann, T. A.
The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nature Rev. Immunol.
6, 595–601 (2006).
Ma, A., Koka, R. & Burkett, P.
Diverse functions of IL-2, IL-15, and IL-7 in lymphoid homeostasis. Annu. Rev. Immunol.
24, 657–679 (2006).
Boyman, O., Cho, J. H. & Sprent, J.
The role of interleukin-2 in memory CD8 cell differentiation. Adv. Exp. Med. Biol.
684, 28–41 (2010).
Kundig, T. M.
et al. Immune responses in interleukin-2-deficient mice. Science
262, 1059–1061 (1993).
Cousens, L. P., Orange, J. S. & Biron, C. A.
Endogenous IL-2 contributes to T cell expansion and IFN-γ production during lymphocytic choriomeningitis virus infection. J. Immunol.
155, 5690–5699 (1995).
D'Souza, W. N. & Lefrancois, L.
IL-2 is not required for the initiation of CD8 T cell cycling but sustains expansion. J. Immunol.
171, 5727–5735 (2003).
Obar, J. J.
et al. CD4+ T cell regulation of CD25 expression controls development of short-lived effector CD8+ T cells in primary and secondary responses. Proc. Natl Acad. Sci. USA
107, 193–198 (2010).
Williams, M. A., Tyznik, A. J. & Bevan, M. J.
Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells. Nature
441, 890–893 (2006).
Bachmann, M. F., Wolint, P., Walton, S., Schwarz, K. & Oxenius, A.
Differential role of IL-2R signaling for CD8+ T cell responses in acute and chronic viral infections. Eur. J. Immunol.
37, 1502–1512 (2007).
Feau, S., Arens, R., Togher, S. & Schoenberger, S. P.
Autocrine IL-2 is required for secondary population expansion of CD8+ memory T cells. Nature Immunol.
12, 908–913 (2011).
et al. Prolonged interleukin-2Rα expression on virus-specific CD8+ T cells favors terminal-effector differentiation in vivo. Immunity
32, 91–103 (2010).
Pipkin, M. E.
et al. Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity
32, 79–90 (2010). References 22, 26 and 27 show that the strength and duration of IL-2 signals determine the fate of effector CD8+ T cells.
et al. mTOR regulates memory CD8 T-cell differentiation. Nature
460, 108–112 (2009).
Boyman, O., Letourneau, S., Krieg, C. & Sprent, J.
Homeostatic proliferation and survival of naive and memory T cells. Eur. J. Immunol.
39, 2088–2094 (2009).
Krieg, C., Boyman, O., Fu, Y. X. & Kaye, J.
B and T lymphocyte attenuator regulates CD8+ T cell-intrinsic homeostasis and memory cell generation. Nature Immunol.
8, 162–171 (2007).
et al. Regulatory CD4+CD25+ T cells restrict memory CD8+ T cell responses. J. Exp. Med.
196, 1585–1592 (2002).
Murakami, M., Sakamoto, A., Bender, J., Kappler, J. & Marrack, P.
CD25+CD4+ T cells contribute to the control of memory CD8+ T cells. Proc. Natl Acad. Sci. USA
99, 8832–8837 (2002).
Pandiyan, P., Zheng, L., Ishihara, S., Reed, J. & Lenardo, M. J.
CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nature Immunol.
8, 1353–1362 (2007).
et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science
322, 271–275 (2008).
Qureshi, O. S.
et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science
332, 600–603 (2011).
Cho, J. H.
et al. An intense form of homeostatic proliferation of naive CD8+ cells driven by IL-2. J. Exp. Med.
204, 1787–1801 (2007).
Cho, J. H., Kim, H. O., Surh, C. D. & Sprent, J.
T cell receptor-dependent regulation of lipid rafts controls naive CD8+ T cell homeostasis. Immunity
32, 214–226 (2010).
Malek, T. R. & Castro, I.
Interleukin-2 receptor signaling: at the interface between tolerance and immunity. Immunity
33, 153–165 (2010).
Yu, A., Zhu, L., Altman, N. H. & Malek, T. R.
A low interleukin-2 receptor signaling threshold supports the development and homeostasis of T regulatory cells. Immunity
30, 204–217 (2009).
Fontenot, J. D., Rasmussen, J. P., Gavin, M. A. & Rudensky, A. Y.
A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nature Immunol.
6, 1142–1151 (2005).
et al. Cutting edge: mechanisms of IL-2-dependent maintenance of functional regulatory T cells. J. Immunol.
185, 6426–6430 (2010).
Rubtsov, Y. P.
et al. Stability of the regulatory T cell lineage in vivo. Science
329, 1667–1671 (2010).
Schallenberg, S., Tsai, P. Y., Riewaldt, J. & Kretschmer, K.
Identification of an immediate Foxp3− precursor to Foxp3+ regulatory T cells in peripheral lymphoid organs of nonmanipulated mice. J. Exp. Med.
207, 1393–1407 (2010).
Chen, Q., Kim, Y. C., Laurence, A., Punkosdy, G. A. & Shevach, E. M.
IL-2 controls the stability of Foxp3 expression in TGF-β-induced Foxp3+ T cells in vivo. J. Immunol.
186, 6329–6337 (2011).
Thornton, A. M. & Shevach, E. M.
CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med.
188, 287–296 (1998).
Letourneau, S., Krieg, C., Pantaleo, G. & Boyman, O.
IL-2- and CD25-dependent immunoregulatory mechanisms in the homeostasis of T-cell subsets. J. Allergy Clin. Immunol.
123, 758–762 (2009).
et al. A regulatory T cell-dependent novel function of CD25 (IL-2Rα) controlling memory CD8+ T cell homeostasis. J. Immunol.
178, 1251–1255 (2007).
Littman, D. R. & Rudensky, A. Y.
Th17 and regulatory T cells in mediating and restraining inflammation. Cell
140, 845–858 (2010).
Liao, W., Lin, J. X., Wang, L., Li, P. & Leonard, W. J.
Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages. Nature Immunol.
12, 551–559 (2011).
Yang, X. P.
et al. Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nature Immunol.
12, 247–254 (2011).
et al. CD4+CD25+Foxp3+ regulatory T cells promote Th17 cells in vitro and enhance host resistance in mouse Candida albicans Th17 cell infection model. Immunity
34, 422–434 (2011).
et al. Foxp3+ regulatory T cells promote T helper 17 cell development in vivo through regulation of interleukin-2. Immunity
34, 409–421 (2011).
Zhu, J., Yamane, H. & Paul, W. E.
Differentiation of effector CD4 T cell populations. Annu. Rev. Immunol.
28, 445–489 (2010).
et al. Interleukin 2 plays a central role in Th2 differentiation. Proc. Natl Acad. Sci. USA
101, 3880–3885 (2004).
et al. Priming for T helper type 2 differentiation by interleukin 2-mediated induction of interleukin 4 receptor α-chain expression. Nature Immunol.
9, 1288–1296 (2008).
Follicular helper CD4 T cells (TFH). Annu. Rev. Immunol.
29, 621–663 (2011).
et al. A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity
29, 127–137 (2008).
Choi, Y. S.
et al. ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6. Immunity
34, 932–946 (2011).
Pepper, M., Pagan, A. J., Igyarto, B. Z., Taylor, J. J. & Jenkins, M. K.
Opposing signals from the Bcl6 transcription factor and the interleukin-2 receptor generate T helper 1 central and effector memory cells. Immunity
35, 583–595 (2011). References 58 and 59 show that the strength and duration of IL-2 signals determine whether activated CD4+ T cells become effector T cells, TFH cells or central memory T cells.
Crowley, M., Inaba, K., Witmer-Pack, M. & Steinman, R. M.
The cell surface of mouse dendritic cells: FACS analyses of dendritic cells from different tissues including thymus. Cell. Immunol.
118, 108–125 (1989).
Freudenthal, P. S. & Steinman, R. M.
The distinct surface of human blood dendritic cells, as observed after an improved isolation method. Proc. Natl Acad. Sci. USA
87, 7698–7702 (1990).
et al. Interleukin 2 receptors on cultured murine epidermal Langerhans cells. J. Immunol.
137, 155–159 (1986).
Kronin, V., Vremec, D. & Shortman, K.
Does the IL-2 receptor α chain induced on dendritic cells have a biological function?
10, 237–240 (1998).
von Bergwelt-Baildon, M. S.
et al. CD25 and indoleamine 2,3-dioxygenase are up-regulated by prostaglandin E2 and expressed by tumor-associated dendritic cells in vivo: additional mechanisms of T-cell inhibition. Blood
108, 228–237 (2006).
Granucci, F., Feau, S., Angeli, V., Trottein, F. & Ricciardi-Castagnoli, P.
Early IL-2 production by mouse dendritic cells is the result of microbial-induced priming. J. Immunol.
170, 5075–5081 (2003).
et al. Dendritic cell-derived IL-2 production is regulated by IL-15 in humans and in mice. Blood
105, 697–702 (2005).
Slack, E. C.
et al. Syk-dependent ERK activation regulates IL-2 and IL-10 production by DC stimulated with zymosan. Eur. J. Immunol.
37, 1600–1612 (2007).
Wuest, S. C.
et al. A role for interleukin-2 trans-presentation in dendritic cell-mediated T cell activation in humans, as revealed by daclizumab therapy. Nature Med.
17, 604–609 (2011). This study suggests that CD25 expressed by DCs can bind and present IL-2 in trans to activated neighbouring T cells in vitro.
Velten, F. W., Rambow, F., Metharom, P. & Goerdt, S.
Enhanced T-cell activation and T-cell-dependent IL-2 production by CD83+, CD25high, CD43high human monocyte-derived dendritic cells. Mol. Immunol.
44, 1544–1550 (2007).
et al. Anti-CD25 antibodies affect cytokine synthesis pattern of human dendritic cells and decrease their ability to prime allogeneic CD4+ T cells. J. Leukoc. Biol.
84, 460–467 (2008).
Miller, J. D., Clabaugh, S. E., Smith, D. R., Stevens, R. B. & Wrenshall, L. E.
Interleukin-2 is present in human blood vessels and released in biologically active form by heparanase. Immunol. Cell Biol.
24 May 2011 (doi:10.1038/icb.2011.45).
Yui, M. A., Sharp, L. L., Havran, W. L. & Rothenberg, E. V.
Preferential activation of an IL-2 regulatory sequence transgene in TCR γδ and NKT cells: subset-specific differences in IL-2 regulation. J. Immunol.
172, 4691–4699 (2004).
McNally, A., Hill, G. R., Sparwasser, T., Thomas, R. & Steptoe, R. J.
CD4+CD25+ regulatory T cells control CD8+ T-cell effector differentiation by modulating IL-2 homeostasis. Proc. Natl Acad. Sci. USA
108, 7529–7534 (2011).
et al. Memory-type CD8+ T cells protect IL-2 receptor α-deficient mice from systemic infection with herpes simplex virus type 2. J. Immunol.
165, 4552–4560 (2000).
et al. The IL-2 receptor present on human embryonic fibroblasts is functional in the absence of P64/IL-2Rγ chain. Int. Immunol.
5, 843–848 (1993).
Gruss, H. J., Scott, C., Rollins, B. J., Brach, M. A. & Herrmann, F.
Human fibroblasts express functional IL-2 receptors formed by the IL-2R α- and β-chain subunits: association of IL-2 binding with secretion of the monocyte chemoattractant protein-1. J. Immunol.
157, 851–857 (1996).
Krieg, C., Letourneau, S., Pantaleo, G. & Boyman, O.
Improved IL-2 immunotherapy by selective stimulation of IL-2 receptors on lymphocytes and endothelial cells. Proc. Natl Acad. Sci. USA
107, 11906–11911 (2010). This paper shows that the beneficial and adverse effects of IL-2 immunotherapy depend on different cell types and thus can be dissected from each other.
Downie, G. H., Ryan, U. S., Hayes, B. A. & Friedman, M.
Interleukin-2 directly increases albumin permeability of bovine and human vascular endothelium in vitro. Am. J. Respir. Cell. Mol. Biol.
7, 58–65 (1992).
Baluna, R., Rizo, J., Gordon, B. E., Ghetie, V. & Vitetta, E. S.
Evidence for a structural motif in toxins and interleukin-2 that may be responsible for binding to endothelial cells and initiating vascular leak syndrome. Proc. Natl Acad. Sci. USA
96, 3957–3962 (1999).
Bae, J., Park, D., Lee, Y. S. & Jeoung, D.
Interleukin-2 promotes angiogenesis by activation of Akt and increase of ROS. J. Microbiol. Biotechnol.
18, 377–382 (2008).
Schulz, O., Sewell, H. F. & Shakib, F.
Proteolytic cleavage of CD25, the α subunit of the human T cell interleukin 2 receptor, by Der p 1, a major mite allergen with cysteine protease activity. J. Exp. Med.
187, 271–275 (1998).
Rubin, L. A. & Nelson, D. L.
The soluble interleukin-2 receptor: biology, function, and clinical application. Ann. Intern. Med.
113, 619–627 (1990).
Lindqvist, C. A.
et al. T regulatory cells control T-cell proliferation partly by the release of soluble CD25 in patients with B-cell malignancies. Immunology
131, 371–376 (2010).
Rubinstein, M. P.
et al. Converting IL-15 to a superagonist by binding to soluble IL-15Rα. Proc. Natl Acad. Sci. USA
103, 9166–9171 (2006).
Yang, Z. Z.
et al. Soluble IL-2Rα facilitates IL-2-mediated immune responses and predicts reduced survival in follicular B-cell non-Hodgkin lymphoma. Blood
118, 2809–2820 (2011).
Rosenberg, S. A.
Progress in human tumour immunology and immunotherapy. Nature
411, 380–384 (2001).
Smith, F. O.
et al. Treatment of metastatic melanoma using interleukin-2 alone or in conjunction with vaccines. Clin. Cancer Res.
14, 5610–5618 (2008).
Klapper, J. A.
et al. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma: a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. Cancer
113, 293–301 (2008).
et al. Interleukin-2 therapy in patients with HIV infection. N. Engl. J. Med.
361, 1548–1559 (2009).
Boyman, O., Surh, C. D. & Sprent, J.
Potential use of IL-2/anti-IL-2 antibody immune complexes for the treatment of cancer and autoimmune disease. Expert Opin. Biol. Ther.
6, 1323–1331 (2006).
Donohue, J. H. & Rosenberg, S. A.
The fate of interleukin-2 after in vivo administration. J. Immunol.
130, 2203–2208 (1983).
McDermott, D. F. & Atkins, M. B.
Application of IL-2 and other cytokines in renal cancer. Expert Opin. Biol. Ther.
4, 455–468 (2004).
et al. Enhancement of anti-tumor activity of recombinant interleukin-2 (rIL-2) by immunocomplexing with a monoclonal antibody against rIL-2. Biotherapy
6, 225–231 (1993).
Courtney, L. P., Phelps, J. L. & Karavodin, L. M.
An anti-IL-2 antibody increases serum half-life and improves anti-tumor efficacy of human recombinant interleukin-2. Immunopharmacology
28, 223–232 (1994).
et al. IL-2/anti-IL-2 antibody complexes show strong biological activity by avoiding interaction with IL-2 receptor α subunit CD25. Proc. Natl Acad. Sci. USA
107, 2171–2176 (2010).
Verdeil, G., Marquardt, K., Surh, C. D. & Sherman, L. A.
Adjuvants targeting innate and adaptive immunity synergize to enhance tumor immunotherapy. Proc. Natl Acad. Sci. USA
105, 16683–16688 (2008).
Jin, G. H., Hirano, T. & Murakami, M.
Combination treatment with IL-2 and anti-IL-2 mAbs reduces tumor metastasis via NK cell activation. Int. Immunol.
20, 783–789 (2008).
Tomala, J., Chmelova, H., Mrkvan, T., Rihova, B. & Kovar, M.
In vivo expansion of activated naive CD8+ T cells and NK cells driven by complexes of IL-2 and anti-IL-2 monoclonal antibody as novel approach of cancer immunotherapy. J. Immunol.
183, 4904–4912 (2009).
Hamilton, S. E., Schenkel, J. M., Akue, A. D. & Jameson, S. C.
IL-2 complex treatment can protect naive mice from bacterial and viral infection. J. Immunol.
185, 6584–6590 (2010).
Molloy, M. J., Zhang, W. & Usherwood, E. J.
Cutting edge: IL-2 immune complexes as a therapy for persistent virus infection. J. Immunol.
182, 4512–4515 (2009).
et al. In vitro-expanded donor alloantigen-specific CD4+CD25+ regulatory T cells promote experimental transplantation tolerance. Blood
109, 827–835 (2007).
Webster, K. E.
et al. In vivo expansion of T reg cells with IL-2–mAb complexes: induction of resistance to EAE and long-term acceptance of islet allografts without immunosuppression. J. Exp. Med.
206, 751–760 (2009).
et al. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity
28, 687–697 (2008).
et al. Expansion of regulatory T cells via IL-2/anti-IL-2 mAb complexes suppresses experimental myasthenia. Eur. J. Immunol.
40, 1577–1589 (2010).
Wilson, M. S.
et al. Suppression of murine allergic airway disease by IL-2:anti-IL-2 monoclonal antibody-induced regulatory T cells. J. Immunol.
181, 6942–6954 (2008).
et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nature Med.
15, 930–939 (2009).
Rabinovitch, A., Suarez-Pinzon, W. L., Shapiro, A. M., Rajotte, R. V. & Power, R.
Combination therapy with sirolimus and interleukin-2 prevents spontaneous and recurrent autoimmune diabetes in NOD mice. Diabetes
51, 638–645 (2002).
Bluestone, J. A.
et al. The Immune Tolerance Network at 10 years: tolerance research at the bedside. Nature
10, 797–803 (2010).
et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N. Engl. J. Med.
365, 2055–2066 (2011).
et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N. Engl. J. Med.
365, 2067–2077 (2011). References 109 and 110 describe early-phase clinical studies showing increased TReg cell frequencies and clinical improvement following low-dose IL-2 immunotherapy in patients with chronic graft-versus-host disease or hepatitis C virus-induced vasculitis.
Ku, C. C., Murakami, M., Sakamoto, A., Kappler, J. & Marrack, P.
Control of homeostasis of CD8+ memory T cells by opposing cytokines. Science
288, 675–678 (2000).
Shanafelt, A. B.
et al. A T-cell-selective interleukin 2 mutein exhibits potent antitumor activity and is well tolerated in vivo. Nature Biotech.
18, 1197–1202 (2000).
Rao, B. M., Driver, I., Lauffenburger, D. A. & Wittrup, K. D.
High-affinity CD25-binding IL-2 mutants potently stimulate persistent T cell growth. Biochemistry
44, 10696–10701 (2005).
Hanke, T., Mitnacht, R., Boyd, R. & Hunig, T.
Induction of interleukin 2 receptor β chain expression by self-recognition in the thymus. J. Exp. Med.
180, 1629–1636 (1994).
Ohteki, T., Ho, S., Suzuki, H., Mak, T. W. & Ohashi, P. S.
Role for IL-15/IL-15 receptor β-chain in natural killer 1.1+ T cell receptor-αβ+ cell development. J. Immunol.
159, 5931–5935 (1997).
Matsuda, J. L.
et al. Homeostasis of Vα 14i NKT cells. Nature Immunol.
3, 966–974 (2002).
Lau-Kilby, A. W.
et al. Interleukin-2 inhibits FMS-like tyrosine kinase 3 receptor ligand (flt3L)-dependent development and function of conventional and plasmacytoid dendritic cells. Proc. Natl Acad. Sci. USA
108, 2408–2413 (2011).