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

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Abstract

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.

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Acknowledgements

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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