1. Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+CD25+ regulatory T cells
- Author
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Charles S. Carter, Hua Zhang, Margaret V. Brown, Brenna J. Hill, Daniel C. Douek, Thomas A. Fleisher, Lauren M. Long, Jay A. Berzofsky, Martin Guimond, Donna Bernstein, Elizabeth J. Read, Kevin S. Chua, Veena Kapoor, Crystal L. Mackall, and Lee J. Helman
- Subjects
Adult ,CD4-Positive T-Lymphocytes ,Interleukin 2 ,Adolescent ,chemical and pharmacologic phenomena ,Biology ,medicine.disease_cause ,T-Lymphocytes, Regulatory ,General Biochemistry, Genetics and Molecular Biology ,Immune tolerance ,Autoimmunity ,Mice ,Immune system ,immune system diseases ,Lymphopenia ,hemic and lymphatic diseases ,medicine ,Animals ,Homeostasis ,Humans ,IL-2 receptor ,Child ,Mice, Knockout ,Autoimmune disease ,Interleukin ,FOXP3 ,Forkhead Transcription Factors ,Receptors, Interleukin-2 ,Sarcoma ,hemic and immune systems ,General Medicine ,Middle Aged ,medicine.disease ,Recombinant Proteins ,Mice, Inbred C57BL ,Lymphocyte Transfusion ,Immunology ,Interleukin-2 ,Female ,medicine.drug - Abstract
CD4(+)CD25(+) regulatory T (T(reg)) cells have a crucial role in maintaining immune tolerance. Mice and humans born lacking T(reg) cells develop severe autoimmune disease, and depletion of T(reg) cells in lymphopenic mice induces autoimmunity. Interleukin (IL)-2 signaling is required for thymic development, peripheral expansion and suppressive activity of T(reg) cells. Animals lacking IL-2 die of autoimmunity, which is prevented by administration of IL-2-responsive T(reg) cells. In light of the emerging evidence that one of the primary physiologic roles of IL-2 is to generate and maintain T(reg) cells, the question arises as to the effects of IL-2 therapy on them. We monitored T(reg) cells during immune reconstitution in individuals with cancer who did or did not receive IL-2 therapy. CD4(+)CD25(hi) cells underwent homeostatic peripheral expansion during immune reconstitution, and in lymphopenic individuals receiving IL-2, the T(reg) cell compartment was markedly increased. Mouse studies showed that IL-2 therapy induced expansion of existent T(reg) cells in normal hosts, and IL-2-induced T(reg) 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 T(reg) cells present in normal hosts. These studies suggest that IL-2 and lymphopenia are primary modulators of CD4(+)CD25(+) T(reg) cell homeostasis.
- Published
- 2005