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

Hua Zhang, Kevin S. Chua, Martin Guimond, Veena Kapoor, Margaret V. Brown, Thomas A. Fleisher, Lauren M. Long, Donna Bernstein, Brenna J. Hill, Daniel C. Douek, Jay A. Berzofsky, Charles S. Carter, E. J. Read, Lee J. Helman, Crystal L. Mackall

Research output: Contribution to journalArticle

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 autoimmunity 3,4. 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, T reg 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.

Original languageEnglish (US)
Pages (from-to)1238-1243
Number of pages6
JournalNature medicine
Volume11
Issue number11
DOIs
StatePublished - Nov 1 2005

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Zhang, H., Chua, K. S., Guimond, M., Kapoor, V., Brown, M. V., Fleisher, T. A., Long, L. M., Bernstein, D., Hill, B. J., Douek, D. C., Berzofsky, J. A., Carter, C. S., Read, E. J., Helman, L. J., & Mackall, C. L. (2005). Lymphopenia and interleukin-2 therapy alter homeostasis of CD4 +CD25+ regulatory T cells. Nature medicine, 11(11), 1238-1243. https://doi.org/10.1038/nm1312