Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases

Key Points

  • Interleukin-2 (IL-2) was discovered as a cytokine that supports the proliferation and differentiation of effector T cells. IL-2 initially entered clinical development based on this activity, in settings such as cancer and infectious diseases.

  • When used at high doses in patients with melanoma or renal cell carcinoma, IL-2 induces relatively rare (around 7%) but durable complete responses, at the expense of severe side effects. IL-2 has been approved by the US Food and Drug Administration for these indications.

  • Surprisingly, knockout of the genes encoding IL-2 or IL-2 receptor in mice led to severe autoimmunity, rather than the predicted immune deficiency. This was later explained by a defect in regulatory T (TReg) cells, and the discovery that IL-2 is the key cytokine for TReg cell function and survival.

  • Further studies showed that IL-2 also favours the development of activated CD4+ T cells towards the T helper 1 (TH1), TH2, TH9 and peripherally induced TReg (pTReg) cell lineages, rather than the TH17 and T follicular helper (TFH) cell lineages. Thus, IL-2 contributes to tipping the immune balance towards regulation rather than inflammation, notably by favouring the differentiation of pTReg cells over TH17 cells; helps to control autoantibody generation by favouring T follicular regulatory cells over TFH cells; and helps to control autoreactive CD8+ effector T cells.

  • Proof-of-concept clinical trials have shown that at a low dose, IL-2 is well tolerated, induces TReg cells and mediates clinical improvements in autoimmune and inflammatory diseases; these findings have been confirmed in additional trials.

  • These trials and additional experimental work also showed that IL-2 mediates immunoregulation without immunosuppression. This opens the door for broad investigation of the therapeutic potential of low-dose IL-2 in a large number of autoimmune and inflammatory diseases.

Abstract

Depletion of regulatory T (TReg) cells in otherwise healthy individuals leads to multi-organ autoimmune disease and inflammation. This indicates that in a normal immune system, there are self-specific effector T cells that are ready to attack normal tissue if they are not restrained by TReg cells. The data imply that there is a balance between effector T cells and TReg cells in health and suggest a therapeutic potential of TReg cells in diseases in which this balance is altered. Proof-of-concept clinical trials, now supported by robust mechanistic studies, have shown that low-dose interleukin-2 specifically expands and activates TReg cell populations and thus can control autoimmune diseases and inflammation.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Pleiotropic effects of interleukin-2 in controlling autoimmunity.
Figure 2: Effector T cells and regulatory T cells show differential use of signalling pathways and differential sensitivity to interleukin-2.
Figure 3: Effects of interleukin-2 in patients with autoimmune or inflammatory diseases.
Figure 4: Possible administration schemes for interleukin-2.

References

  1. Sakaguchi, S., Powrie, F. & Ransohoff, R. M. Re-establishing immunological self-tolerance in autoimmune disease. Nature Med. 18, 54–58 (2012).

    Article  CAS  PubMed  Google Scholar 

  2. Shevach, E. M. & Thornton, A. M. tTregs, pTregs, and iTregs: similarities and differences. Immunol. Rev. 259, 88–102 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Moraes-Vasconcelos, D., Costa-Carvalho, B. T., Torgerson, T. R. & Ochs, H. D. Primary immune deficiency disorders presenting as autoimmune diseases: IPEX and APECED. J. Clin. Immunol. 28 (Suppl. 1), 11–19 (2008).

    Article  CAS  Google Scholar 

  4. Godfrey, V., Wilkinson, J. & Russell, L. X-linked lymphoreticular disease in the scurfy (sf) mutant mouse. Am. J. Pathol. 138, 1379–1387 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Noack, M. & Miossec, P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev. 13, 668–677 (2014).

    Article  CAS  PubMed  Google Scholar 

  6. Kim, J. M., Rasmussen, J. P. & Rudensky, A. Y. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nature Immunol. 8, 191–197 (2007). T Reg cell depletion in otherwise healthy individuals triggers brisk autoimmune responses, underscoring the permanent suppression of potentially harmful effector T cells that occurs during homeostasis.

    Article  CAS  Google Scholar 

  7. Marek-Trzonkowska, N. et al. Administration of CD4+CD25highCD127 regulatory T cells preserves β-cell function in type 1 diabetes in children. Diabetes Care 35, 1817–1820 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Malek, T. R. The biology of interleukin-2. Annu. Rev. Immunol. 26, 453–479 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Boyman, O. & Sprent, J. The role of interleukin-2 during homeostasis and activation of the immune system. Nature Rev. Immunol. 12, 180–190 (2012).

    Article  CAS  Google Scholar 

  10. Liao, W., Lin, J. X. & Leonard, W. J. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity 38, 13–25 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Saadoun, D. et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N. Engl. J. Med. 365, 2067–2077 (2011). The first clinical trial showing that low-dose IL-2 is safe and clinically efficacious, and that it induces T Reg cells, in an autoimmune disease.

    Article  CAS  PubMed  Google Scholar 

  12. Koreth, J. et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N. Engl. J. Med. 365, 2055–2066 (2011). The first clinical trial showing that low-dose IL-2 is safe and clinically efficacious, and that it induces T Reg cells, in an alloimmune inflammatory disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Robb, R. J. Interleukin 2: the molecule and its function. Immunol. Today 5, 203–209 (1984).

    Article  CAS  PubMed  Google Scholar 

  14. Sadlack, B. et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75, 253–261 (1993). The first evidence that IL-2 is involved in preventing autoimmune diseases.

    Article  CAS  PubMed  Google Scholar 

  15. Suzuki, H. et al. Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor β. Science 268, 1472–1476 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. Willerford, D. M. et al. Interleukin-2 receptor α chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3, 521–530 (1995).

    Article  CAS  PubMed  Google Scholar 

  17. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155, 1151–1164 (1995). The discovery of T Reg cells and their role in preventing autoimmune diseases.

    CAS  PubMed  Google Scholar 

  18. Malek, T. R., Yu, A., Vincek, V., Scibelli, P. & Kong, L. CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rβ-deficient mice. Implications for the nonredundant function of IL-2. Immunity 17, 167–178 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Vang, K. B. et al. IL-2, -7, and -15, but not thymic stromal lymphopoeitin, redundantly govern CD4+Foxp3+ regulatory T cell development. J. Immunol. 181, 3285–3290 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. 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).

    Article  CAS  Google Scholar 

  21. Barron, L. et al. Cutting edge: mechanisms of IL-2-dependent maintenance of functional regulatory T cells. J. Immunol. 185, 6426–6430 (2010).

    Article  CAS  PubMed  Google Scholar 

  22. Feng, Y. et al. Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus. Cell 158, 749–763 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ohkura, N. et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity 37, 785–799 (2012).

    Article  CAS  PubMed  Google Scholar 

  24. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kalia, V. et al. Prolonged interleukin-2Rα expression on virus-specific CD8+ T cells favors terminal-effector differentiation in vivo. Immunity 32, 91–103 (2010).

    Article  CAS  PubMed  Google Scholar 

  26. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bilate, A. M. & Lafaille, J. J. Induced CD4+Foxp3+ regulatory T cells in immune tolerance. Annu. Rev. Immunol. 30, 733–758 (2012).

    Article  CAS  PubMed  Google Scholar 

  29. Cote-Sierra, J. et al. Interleukin 2 plays a central role in TH2 differentiation. Proc. Natl Acad. Sci. USA 101, 3880–3885 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Liao, W. et al. Opposing actions of IL-2 and IL-21 on Th9 differentiation correlate with their differential regulation of BCL6 expression. Proc. Natl Acad. Sci. USA 111, 3508–3513 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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).

    Article  CAS  Google Scholar 

  32. Laurence, A. et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26, 371–381 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Ballesteros-Tato, A. et al. Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 36, 847–856 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Linterman, M. A. et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nature Med. 17, 975–982 (2011).

    Article  CAS  PubMed  Google Scholar 

  35. Chung, Y. et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nature Med. 17, 983–988 (2011).

    Article  CAS  PubMed  Google Scholar 

  36. Wollenberg, I. et al. Regulation of the germinal center reaction by Foxp3+ follicular regulatory T cells. J. Immunol. 187, 4553–4560 (2011).

    Article  CAS  PubMed  Google Scholar 

  37. Neill, D. R. et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367–1370 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Roediger, B. et al. Cutaneous immunosurveillance and regulation of inflammation by group 2 innate lymphoid cells. Nature Immunol. 14, 564–573 (2013).

    Article  CAS  Google Scholar 

  39. Van Gool, F. et al. Interleukin-5 producing group 2 innate lymphoid cells (ILC2) control eosinophilia induced by interleukin-2 therapy. Blood 124, 3572–3576 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ribot, J. C., Ribeiro, S. T., Correia, D. V., Sousa, A. E. & Silva-Santos, B. Human γδ thymocytes are functionally immature and differentiate into cytotoxic type 1 effector T cells upon IL-2/IL-15 signaling. J. Immunol. 192, 2237–2243 (2014).

    Article  CAS  PubMed  Google Scholar 

  41. 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). The molecular explanation for the specific effects of low-dose IL-2 on T Reg cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yu, A. et al. Selective IL-2 responsiveness of regulatory T cells through multiple intrinsic mechanisms support the use of low-dose IL-2 therapy in type-1 diabetes. Diabetes http://dx.doi.org/10.2337/db14-1322 (2015).

  43. Bensinger, S. J. et al. Distinct IL-2 receptor signaling pattern in CD4+CD25+ regulatory T cells. J. Immunol. 172, 5287–5296 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Walsh, P. T. et al. PTEN inhibits IL-2 receptor-mediated expansion of CD4+ CD25+ Tregs. J. Clin. Invest. 116, 2521–2531 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Contractor, N. V. et al. Lymphoid hyperplasia, autoimmunity, and compromised intestinal intraepithelial lymphocyte development in colitis-free gnotobiotic IL-2-deficient mice. J. Immunol. 160, 385–394 (1998).

    CAS  PubMed  Google Scholar 

  46. Schultz, M. et al. IL-2-deficient mice raised under germfree conditions develop delayed mild focal intestinal inflammation. Am. J. Physiol. 276, G1461–G1472 (1999).

    CAS  PubMed  Google Scholar 

  47. Sharfe, N., Dadi, H. K., Shahar, M. & Roifman, C. M. Human immune disorder arising from mutation of the α chain of the interleukin-2 receptor. Proc. Natl Acad. Sci. USA 94, 3168–3171 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Smigiel, K. S. et al. CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets. J. Exp. Med. 211, 121–136 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Gratz, I. K. et al. Cutting edge: memory regulatory T cells require IL-7 and not IL-2 for their maintenance in peripheral tissues. J. Immunol. 190, 4483–4487 (2013).

    Article  CAS  PubMed  Google Scholar 

  50. Raynor, J. et al. IL-15 fosters age-driven regulatory T cell accrual in the face of declining IL-2 levels. T Cell Biol. 4, 161 (2013).

    CAS  Google Scholar 

  51. Zier, K. S., Leo, M. M., Spielman, R. S. & Baker, L. Decreased synthesis of interleukin-2 (IL-2) in insulin-dependent diabetes mellitus. Diabetes 33, 552–555 (1984).

    Article  CAS  PubMed  Google Scholar 

  52. Kitas, G. D., Salmon, M., Farr, M., Gaston, J. S. & Bacon, P. A. Deficient interleukin 2 production in rheumatoid arthritis: association with active disease and systemic complications. Clin. Exp. Immunol. 73, 242–249 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Lieberman, L. A. & Tsokos, G. C. The IL-2 defect in systemic lupus erythematosus disease has an expansive effect on host immunity. J. Biomed. Biotechnol. 2010, 740619 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. 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). The first report of the properties of IL-2–antibody complexes.

    Article  CAS  PubMed  Google Scholar 

  55. Rouse, M., Nagarkatti, M. & Nagarkatti, P. S. The role of IL-2 in the activation and expansion of regulatory T-cells and the development of experimental autoimmune encephalomyelitis. Immunobiology 218, 674–682 (2013).

    Article  CAS  PubMed  Google Scholar 

  56. Hao, J. et al. Interleukin-2/interleukin-2 antibody therapy induces target organ natural killer cells that inhibit central nervous system inflammation. Ann. Neurol. 69, 721–734 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Grinberg-Bleyer, Y. et al. IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells. J. Exp. Med. 207, 1871–1878 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Mizui, M. et al. IL-2 protects lupus-prone mice from multiple end-organ damage by limiting CD4CD8 IL-17-producing T cells. J. Immunol. 193, 2168–2177 (2014).

    Article  CAS  PubMed  Google Scholar 

  59. Tang, Q. et al. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity 28, 687–697 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Liu, R. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ait-Oufella, H. et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nature Med. 12, 178–180 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Mack, D. G. et al. Regulatory T cells modulate granulomatous inflammation in an HLA-DP2 transgenic murine model of beryllium-induced disease. Proc. Natl Acad. Sci. USA 111, 8553–8558 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Villalta, S. A. et al. Regulatory T cells suppress muscle inflammation and injury in muscular dystrophy. Sci. Transl. Med. 6, 258ra142 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Taniguchi, T. et al. Structure and expression of a cloned cDNA for human interleukin-2. Nature 302, 305–310 (1983).

    Article  CAS  PubMed  Google Scholar 

  65. Bindon, C. et al. Clearance rates and systemic effects of intravenously administered interleukin 2 (IL-2) containing preparations in human subjects. Br. J. Cancer 47, 123–133 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Lotze, M. T., Frana, L. W., Sharrow, S. O., Robb, R. J. & Rosenberg, S. A. In vivo administration of purified human interleukin 2. I. Half-life and immunologic effects of the Jurkat cell line-derived interleukin 2. J. Immunol. 134, 157–166 (1985).

    CAS  PubMed  Google Scholar 

  67. Rosenberg, S. A. et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N. Engl. J. Med. 313, 1485–1492 (1985).

    Article  CAS  PubMed  Google Scholar 

  68. Rosenberg, S. A. et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 271, 907–913 (1994). A large study of high-dose IL-2 in patients with cancer.

    Article  CAS  PubMed  Google Scholar 

  69. Yang, J. C. et al. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J. Clin. Oncol. 21, 3127–3132 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. Rosenberg, S. A. IL-2: the first effective immunotherapy for human cancer. J. Immunol. 192, 5451–5458 (2014).

    Article  CAS  PubMed  Google Scholar 

  71. Ahmadzadeh, M. & Rosenberg, S. A. IL-2 administration increases CD4+ CD25hi Foxp3+ regulatory T cells in cancer patients. Blood 107, 2409–2414 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Zhang, H. et al. Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+CD25+ regulatory T cells. Nature Med. 11, 1238–1243 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Lemoine, F. M. et al. Massive expansion of regulatory T-cells following interleukin 2 treatment during a Phase I–II dendritic cell-based immunotherapy of metastatic renal cancer. Int. J. Oncol. 35, 569–581 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. Weiss, L. et al. In vivo expansion of naive and activated CD4+CD25+FOXP3+ regulatory T cell populations in interleukin-2-treated HIV patients. Proc. Natl Acad. Sci. USA 107, 10632–10637 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. London, N. R. et al. Targeting Robo4-dependent Slit signaling to survive the cytokine storm in sepsis and influenza. Sci. Transl. Med. 2, 23ra19 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Ferrara, J. L. Cytokine dysregulation as a mechanism of graft versus host disease. Curr. Opin. Immunol. 5, 794–799 (1993).

    Article  CAS  PubMed  Google Scholar 

  78. Boyer, O. et al. CD4+CD25+ regulatory T-cell deficiency in patients with hepatitis C-mixed cryoglobulinemia vasculitis. Blood 103, 3428–3430 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Saadoun, D. et al. Restoration of peripheral immune homeostasis after rituximab in mixed cryoglobulinemia vasculitis. Blood 111, 5334–5341 (2008).

    Article  CAS  PubMed  Google Scholar 

  80. Landau, D.-A. et al. Correlation of clinical and virologic responses to antiviral treatment and regulatory T cell evolution in patients with hepatitis C virus-induced mixed cryoglobulinemia vasculitis. Arthritis Rheum. 58, 2897–2907 (2008).

    Article  PubMed  Google Scholar 

  81. Alric, L. et al. Pilot study of interferon-α-ribavirin-interleukin-2 for treatment of nonresponder patients with severe liver disease infected by hepatitis C virus genotype 1. J. Viral Hepat. 13, 139–144 (2006).

    Article  CAS  PubMed  Google Scholar 

  82. Hartemann, A. et al. Low-dose interleukin 2 in patients with type 1 diabetes: a Phase 1/2 randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 1, 295–305 (2013).

    Article  CAS  PubMed  Google Scholar 

  83. Castela, E. et al. Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata. JAMA Dermatol. 150, 748–751 (2014).

    Article  CAS  PubMed  Google Scholar 

  84. Kennedy-Nasser, A. A. et al. Ultra low-dose IL-2 for GVHD prophylaxis after allogeneic hematopoietic stem cell transplantation mediates expansion of regulatory T cells without diminishing antiviral and antileukemic activity. Clin. Cancer Res. 20, 2215–2225 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Rosenzwajg, M. et al. Low-dose interleukin-2 fosters a dose-dependent regulatory-tuned milieu in T1D patients. J. Autoimmun. 58, 48–58 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Ito, S. et al. Ultra-low dose interleukin-2 promotes immune-modulating function of regulatory T cells and natural killer cells in healthy volunteers. Mol. Ther. J. Am. Soc. Gene Ther. 22, 1388–1395 (2014).

    Article  CAS  Google Scholar 

  87. Matsuoka, K. et al. Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease. Sci. Transl. Med. 5, 179ra43 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Aoyama, A. et al. Low-dose IL-2 for in vivo expansion of CD4+ and CD8+ regulatory T cells in nonhuman primates. Am. J. Transpl. 12, 2532–2537 (2012).

    Article  CAS  Google Scholar 

  89. Chaput, N. et al. Identification of CD8+CD25+Foxp3+ suppressive T cells in colorectal cancer tissue. Gut 58, 520–529 (2009).

    Article  CAS  PubMed  Google Scholar 

  90. Humrich, J. Y. et al. Rapid induction of clinical remission by low-dose interleukin-2 in a patient with refractory SLE. Ann. Rheum. Dis. 74, 791–792 (2015).

    Article  PubMed  Google Scholar 

  91. Gutierrez-Ramos, J. C., Andreu, J. L., Revilla, Y., Vinuela, E. & Martinez, C. Recovery from autoimmunity of MRL/lpr mice after infection with an interleukin-2/vaccinia recombinant virus. Nature 346, 271–274 (1990).

    Article  CAS  PubMed  Google Scholar 

  92. Goudy, K. S. et al. Inducible adeno-associated virus-mediated IL-2 gene therapy prevents autoimmune diabetes. J. Immunol. 186, 3779–3786 (2011).

    Article  CAS  PubMed  Google Scholar 

  93. Churlaud, G. et al. Sustained stimulation and expansion of Tregs by IL-2 control autoimmunity without impairing immune responses to infection, vaccination and cancer. Clin. Immunol. 151, 114–126 (2014).

    Article  CAS  PubMed  Google Scholar 

  94. Yamaguchi, T., Wing, J. B. & Sakaguchi, S. Two modes of immune suppression by Foxp3+ regulatory T cells under inflammatory or non-inflammatory conditions. Semin. Immunol. 23, 424–430 (2011).

    Article  CAS  PubMed  Google Scholar 

  95. Billiard, F. et al. Regulatory and effector T cell activation levels are prime determinants of in vivo immune regulation. J. Immunol. 177, 2167–2174 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. Sakaguchi, S., Vignali, D. A. A., Rudensky, A. Y., Niec, R. E. & Waldmann, H. The plasticity and stability of regulatory T cells. Nature Rev. Immunol. 13, 461–467 (2013).

    Article  CAS  Google Scholar 

  97. Van Loosdregt, J. et al. Stabilization of the transcription factor Foxp3 by the deubiquitinase USP7 increases Treg-cell-suppressive capacity. Immunity 39, 259–271 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Chen, Z. et al. The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3. Immunity 39, 272–285 (2013).

    Article  CAS  PubMed  Google Scholar 

  99. Li, Z. et al. PIM1 kinase phosphorylates the human transcription factor FOXP3 at serine 422 to negatively regulate its activity under inflammation. J. Biol. Chem. 289, 26872–26881 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Li, C. et al. MeCP2 enforces Foxp3 expression to promote regulatory T cells' resilience to inflammation. Proc. Natl Acad. Sci. USA 111, E2807–E2816 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Dietrich, T. et al. Local delivery of IL-2 reduces atherosclerosis via expansion of regulatory T cells. Atherosclerosis 220, 329–336 (2012).

    Article  CAS  PubMed  Google Scholar 

  102. Dinh, T. N. et al. Cytokine therapy with interleukin-2/anti-interleukin-2 monoclonal antibody complexes expands CD4+CD25+Foxp3+ regulatory T cells and attenuates development and progression of atherosclerosis. Circulation 126, 1256–1266 (2012).

    Article  CAS  PubMed  Google Scholar 

  103. D'Alessio, F. R. et al. CD4+CD25+Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury. J. Clin. Invest. 119, 2898–2913 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. 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).

    Article  CAS  PubMed  Google Scholar 

  105. Rosenberg, H. F., Dyer, K. D. & Foster, P. S. Eosinophils: changing perspectives in health and disease. Nature Rev. Immunol. 13, 9–22 (2013).

    Article  CAS  Google Scholar 

  106. Oliphant, C. J. et al. MHCII-mediated dialog between group 2 innate lymphoid cells and CD4+ T cells potentiates type 2 immunity and promotes parasitic helminth expulsion. Immunity 41, 283–295 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Zheng, X. X. et al. Favorably tipping the balance between cytopathic and regulatory T cells to create transplantation tolerance. Immunity 19, 503–514 (2003).

    Article  CAS  PubMed  Google Scholar 

  108. Blackman, M. A. & Woodland, D. L. The narrowing of the CD8 T cell repertoire in old age. Curr. Opin. Immunol. 23, 537–542 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Thomas-Vaslin, V. et al. in Immunosuppression — Role in Health and Diseases. (eds Kapur, S. & Portela, M. B.) 125–147 (Intech, 2012).

    Google Scholar 

  110. Harvill, E. T. & Morrison, S. L. An IgG3-IL2 fusion protein activates complement, binds Fcγ RI, generates LAK activity and shows enhanced binding to the high affinity IL-2R. Immunotechnol. Int. J. Immunol. Eng. 1, 95–105 (1995).

    Article  CAS  Google Scholar 

  111. 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).

    Article  CAS  Google Scholar 

  112. Levin, A. M. et al. Exploiting a natural conformational switch to engineer an interleukin-2 'superkine'. Nature 484, 529–533 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Rosalia, R. A., Arenas-Ramirez, N., Bouchaud, G., Raeber, M. E. & Boyman, O. Use of enhanced interleukin-2 formulations for improved immunotherapy against cancer. Curr. Opin. Chem. Biol. 23, 39–46 (2014).

    Article  CAS  PubMed  Google Scholar 

  114. Kaufman, H. L. et al. The society for immunotherapy of cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma. Nature Rev. Clin. Oncol. 10, 588–598 (2013).

    Article  CAS  Google Scholar 

  115. Kasakura, S. & Lowenstein, L. A factor stimulating DNA synthesis derived from the medium of leukocyte cultures. Nature 208, 794–795 (1965).

    Article  CAS  PubMed  Google Scholar 

  116. Gordon, J. & MacLean, L. D. A lymphocyte-stimulating factor produced in vitro. Nature 208, 795–796 (1965).

    Article  CAS  PubMed  Google Scholar 

  117. 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). The first evidence of a T cell growth factor (IL-2) produced by activated T cells.

    Article  CAS  PubMed  Google Scholar 

  118. Gillis, S., Baker, P. E., Ruscetti, F. W. & Smith, K. A. Long-term culture of human antigen-specific cytotoxic T-cell lines. J. Exp. Med. 148, 1093–1098 (1978).

    Article  CAS  PubMed  Google Scholar 

  119. Smith, K. A. Interleukin-2: inception, impact, and implications. Science 240, 1169–1176 (1988).

    Article  CAS  PubMed  Google Scholar 

  120. Edwards, I. R. & Aronson, J. K. Adverse drug reactions: definitions, diagnosis, and management. Lancet 356, 1255–1259 (2000).

    Article  CAS  PubMed  Google Scholar 

  121. Prometheus Laboratories. Proleukin® (aldesleukin). [online], (2012).

  122. Churlaud, G. et al. Human and mouse CD8+CD25+FOXP3+ regulatory T cells at steady state and during interleukin-2 therapy. Front. Immunol. http://dx.doi.org/10.3389/fimmu.2015.00171 (2015).

Download references

Acknowledgements

The work of D.K. is funded by French state funds within the Investissements d'Avenir programme (ANR-11-IDEX-0004-02; LabEx Transimmunom); the European Research Council Advanced Grant (ERC-2012-AdG, TRiPoD, Agreement number 322856); the Assistance Publique – Hopitaux de Paris, France; the Sorbonne University, Pierre and Marie Curie Medical School, Paris, France; the Institut National de la Santé et de la Recherche Médicale (INSERM); and Le Centre National de la Recherche Scientifique (CNRS).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to David Klatzmann or Abul K. Abbas.

Ethics declarations

Competing interests

D.K. is an inventor of a patent application claiming low-dose IL-2 for therapy of autoimmune diseases, owned by his academic institution, and licensed to ILTOO Pharma, which he advises and in which he holds shares. A.K.A. declares no competing interests.

Related links

PowerPoint slides

Supplementary information

Supplementary information S1 (table)

Main clinical and biological findings from high- to low-dose IL-2 clinical trials (PDF 269 kb)

Glossary

T follicular regulatory cells

(TFR cells). Cells that are derived from thymus-derived regulatory T cells and share phenotypic characteristics with T follicular helper (TFH) cells, including the expression of the B cell follicle-homing receptor CXC-chemokine receptor 5. TFH cells control germinal centre B cells undergoing somatic hypermutation and selection that results in antibody affinity maturation. TFR cells reduce TFH cell and germinal centre B cell numbers.

Type 2 innate lymphoid cells

(ILC2s). ILCs are rare cells from the lymphoid lineage — comprising the ILC1, ILC2 and ILC3 subsets — that produce many of the same cytokines as T cells but lack T cell antigen receptors. They have diverse roles in immune responses and inflammation. ILC2s produce type 2 cytokines, such as interleukin-5 (IL-5) and IL-13, and have key roles in anthelminthic responses and allergic lung inflammation.

IL-2 international units

(IL-2 IU). The interleukin-2 (IL-2) IU is a biological activity determined by the ability to support the growth of an IL-2-dependent cell line. In practice, as the manufacture of IL-2 is standardized, 1.1 mg of IL-2 corresponds to 18 million IU.

Immune dysregulation polyendocrinopathy enteropathy X-linked syndrome

(IPEX syndrome). This rare genetic autoimmune disease is caused by mutations in the FOXP3 gene (which encodes forkhead box P3). Affected males present with early-onset severe enteropathy that is usually accompanied by insulin-dependent diabetes (type 1). Other autoimmune manifestations include hypothyroidism, anaemia, thrombocytopenia and neutropenia. Increased serum IgE levels and dermatitis are often also present.

IL-2–antibody complex

(IL-2c). A complex of interleukin-2 (IL-2) and IL-2-specific antibody that has a prolonged half-life compared with IL-2. Its biological activity depends on the antibody. Some complexes preferentially stimulate effector T cells, whereas others preferentially stimulate regulatory T cells.

Vascular leak syndrome

(VLS). VLS (also known as capillary leak syndrome, systemic capillary leak syndrome or Clarkson disease) is characterized by a leakage of fluid from the circulatory system into the interstitial space, resulting in hypotension, haemoconcentration and hypoalbuminaemia.

Cytokine storm

Also known as hypercytokinaemia. The systemic expression of a vigorous immune response resulting in the release of inflammatory mediators into the bloodstream, including cytokines, oxygen free radicals and coagulation factors. The primary symptoms of a cytokine storm are high fever, swelling and redness caused by vascular leak, extreme fatigue and nausea.

Graft-versus-host disease

(GVHD). A common complication of allogeneic stem cell transplantation, in which immune cells from the graft recognize the recipient cells as foreign and attack them. The main target tissues are the liver, skin and gastrointestinal tract. It can be acute (within 100 days of transplantation) and life-threatening, or chronic.

Hepatitis C virus-induced vasculitis

(HCV-induced vasculitis). 10–15% of patients with chronic HCV infection develop systemic cryoglobulinaemic vasculitis. Cryoglobulins are cold-insoluble immune complexes containing rheumatoid factor and polyclonal IgG that deposit on vascular endothelium, causing vasculitis in organs such as the skin and kidneys, and in peripheral nerves.

Adverse events

Medical occurrences that are temporally (but not necessarily causally) associated with the use of a medicinal product. The severity of adverse events is graded from 1 to 4, with the grades representing mild, moderate, severe and potentially life-threatening events, respectively. Any adverse event that causes death, is life threatening, requires hospitalization, or results in persistent or significant disability or incapacity is considered a serious adverse event.

Alopecia areata

A prevalent autoimmune disease (affecting 1.7% of the general population) that leads to hair loss on the scalp and other areas of the body. Infiltration of CD4+ and CD8+ T cells around hair follicles is associated with the condition.

TRANSREG clinical trial

An open-label Phase II clinical trial investigating the stimulation of regulatory T cells by low-dose interleukin-2 in 11 autoimmune diseases: rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Behcet disease, Wegener granulomatosis, Takayasu disease, Crohn disease, ulcerative colitis, autoimmune hepatitis and sclerosing cholangitis (ClinicalTrials.gov identifier: NCT01988506).

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Klatzmann, D., Abbas, A. The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nat Rev Immunol 15, 283–294 (2015). https://doi.org/10.1038/nri3823

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri3823

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing