Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+CD25+ regulatory T cells

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CD4+CD25+ regulatory T (Treg) cells have a crucial role in maintaining immune tolerance. Mice and humans born lacking Treg cells develop severe autoimmune disease1,2, and depletion of Treg cells in lymphopenic mice induces autoimmunity3,4. Interleukin (IL)-2 signaling is required for thymic development5, peripheral expansion6 and suppressive activity of Treg cells7. Animals lacking IL-2 die of autoimmunity8,9, which is prevented by administration of IL-2–responsive Treg cells5. In light of the emerging evidence that one of the primary physiologic roles of IL-2 is to generate and maintain Treg cells10, the question arises as to the effects of IL-2 therapy on them. We monitored Treg cells during immune reconstitution in individuals with cancer who did or did not receive IL-2 therapy. CD4+CD25hi cells underwent homeostatic peripheral expansion during immune reconstitution, and in lymphopenic individuals receiving IL-2, the Treg cell compartment was markedly increased. Mouse studies showed that IL-2 therapy induced expansion of existent Treg cells in normal hosts, and IL-2–induced Treg cell expansion was further augmented by lymphopenia. On a per-cell basis, Treg cells generated by IL-2 therapy expressed similar levels of FOXP3 and had similar potency for suppression compared to Treg cells present in normal hosts. These studies suggest that IL-2 and lymphopenia are primary modulators of CD4+CD25+ Treg cell homeostasis.

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Figure 1: Cyclophosphamide-based chemotherapy does not selectively deplete CD4+CD25hi cells.
Figure 2: IL-2 therapy expands the CD4+CD25hi subset.
Figure 3: CD4+CD25hi cells undergo homeostatic peripheral expansion, which is augmented by IL-2 therapy.
Figure 4: IL-2 therapy expands FOXP3 expressing CD4+CD25hi cells with suppressive activity.


  1. 1

    Bennett, C.L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27, 20–21 (2001).

  2. 2

    Brunkow, M.E. et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat. Genet. 27, 68–73 (2001).

  3. 3

    Shevach, E.M. Regulatory T cells in autoimmmunity*. Annu. Rev. Immunol. 18, 423–449 (2000).

  4. 4

    Sakaguchi, S. et al. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol. Rev. 182, 18–32 (2001).

  5. 5

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

  6. 6

    Bayer, A.L., Yu, A., Adeegbe, D. & Malek, T.R. Essential role for interleukin-2 for CD4(+)CD25(+) T regulatory cell development during the neonatal period. J. Exp. Med. 201, 769–777 (2005).

  7. 7

    Furtado, G.C., Curotto de Lafaille, M.A., Kutchukhidze, N. & Lafaille, J.J. Interleukin 2 signaling is required for CD4(+) regulatory T cell function. J. Exp. Med. 196, 851–857 (2002).

  8. 8

    Sadlack, B. et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75, 253–261 (1993).

  9. 9

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

  10. 10

    Malek, T.R. & Bayer, A.L. Tolerance, not immunity, crucially depends on IL-2. Nat. Rev. Immunol. 4, 665–674 (2004).

  11. 11

    Atkins, M.B. Interleukin-2: clinical applications. Semin. Oncol. 29, 12–17 (2002).

  12. 12

    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).

  13. 13

    Melchionda, F. et al. Adjuvant IL-7 or IL-15 overcomes immunodominance and improves survival of the CD8(+) memory cell pool. J. Clin. Invest. 115, 1177–1187 (2005).

  14. 14

    Baecher-Allan, C., Brown, J.A., Freeman, G.J. & Hafler, D.A. CD4+CD25 high regulatory cells in human peripheral blood. J. Immunol. 167, 1245–1253 (2001).

  15. 15

    Katlama, C. et al. Interleukin-2 accelerates CD4 cell reconstitution in HIV-infected patients with severe immunosuppression despite highly active antiretroviral therapy: the ILSTIM study–ANRS 082. AIDS 16, 2027–2034 (2002).

  16. 16

    Sereti, I. et al. In vivo expansion of CD4CD45RO-CD25 T cells expressing foxP3 in IL-2-treated HIV-infected patients. J. Clin. Invest. 115, 1839–1847 (2005).

  17. 17

    Hakim, F.T. et al. Age-dependent incidence, time course, and consequences of thymic renewal in adults. J. Clin. Invest. 115, 930–939 (2005).

  18. 18

    Itoh, M. et al. Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J. Immunol. 162, 5317–5326 (1999).

  19. 19

    Hsieh, C.S. et al. Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity 21, 267–277 (2004).

  20. 20

    Apostolou, I. & von Boehmer, H. In vivo instruction of suppressor commitment in naive T cells. J. Exp. Med. 199, 1401–1408 (2004).

  21. 21

    McHugh, R.S. et al. CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 16, 311–323 (2002).

  22. 22

    Nakamura, K. et al. TGF-beta 1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice. J. Immunol. 172, 834–842 (2004).

  23. 23

    Fry, T.J. et al. A potential role for interleukin-7 in T-cell homeostasis. Blood 97, 2983–2990 (2001).

  24. 24

    Khattri, R., Cox, T., Yasayko, S.A. & Ramsdell, F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat. Immunol. 4, 337–342 (2003).

  25. 25

    Fontenot, J.D. et al. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22, 329–341 (2005).

  26. 26

    Dudley, M.E. et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298, 850–854 (2002).

  27. 27

    Cozzo, C., Larkin, J., III & Caton, A.J. Cutting edge: self-peptides drive the peripheral expansion of CD4+CD25+ regulatory T cells. J. Immunol. 171, 5678–5682 (2003).

  28. 28

    Wang, H.Y. et al. Tumor-specific human CD4+ regulatory T cells and their ligands: implications for immunotherapy. Immunity 20, 107–118 (2004).

  29. 29

    Turk, M.J. et al. Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells. J. Exp. Med. 200, 771–782 (2004).

  30. 30

    Yu, P. et al. Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. J. Exp. Med. 201, 779–791 (2005).

  31. 31

    Douek, D.C. et al. Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution. Lancet 355, 1875–1881 (2000).

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This research was supported in part by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research and by the Children's Cancer Foundation. The authors would like to thank the participants who enrolled on this investigational trial and provided consent for research studies and the clinical staff of the Pediatric Oncology Branch for care of these individuals. We would also like to thank Chiron for supplying recombinant human IL-2 used in this trial, S. Steinberg for statistical support and E. Shevach and S.A. Rosenberg for helpful comments and careful reviews of the manuscript.

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Correspondence to Crystal L Mackall.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Patient data. (PDF 23 kb)

Supplementary Table 2

Immunotherapy administered. (PDF 11 kb)

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Zhang, H., Chua, K., Guimond, M. et al. Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+CD25+ regulatory T cells. Nat Med 11, 1238–1243 (2005) doi:10.1038/nm1312

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