Abstract
IL-2 controls the survival of regulatory T cells (Tregs), but it is unclear whether IL-2 also directly affects Treg suppressive capacity in vivo. We have found that eliminating Bim-dependent apoptosis in IL-2- and CD25-deficient mice restored Treg numbers but failed to cure their lethal autoimmune disease, demonstrating that IL-2-dependent survival and suppressive activity can be uncoupled in Tregs. Treatment with IL-2-anti-IL-2-Ab complexes enhanced the numbers and suppressive capacity of IL-2-deprived Tregs with striking increases in CD25, CTLA-4, and CD39/CD73 expression. Although cytokine treatment induced these suppressive mechanisms in both IL-2(-/-) and IL-2(-/-)Bim(-/-) mice, it only reversed autoimmune disease in the latter. Our results suggest that successful IL-2 therapy of established autoimmune diseases will require a threshold quantity of Tregs present at the start of treatment and show that the suppressive capacity of Tregs critically depends on IL-2 even when Treg survival is independent of this cytokine.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Anemia, Hemolytic, Autoimmune / genetics
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Anemia, Hemolytic, Autoimmune / immunology
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Anemia, Hemolytic, Autoimmune / therapy
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Animals
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Apoptosis Regulatory Proteins / deficiency
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Apoptosis Regulatory Proteins / genetics
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Bcl-2-Like Protein 11
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Cell Proliferation
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Cells, Cultured
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Coculture Techniques
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Forkhead Transcription Factors / deficiency
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Forkhead Transcription Factors / genetics
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Gene Deletion
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Interleukin-2 / genetics
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Interleukin-2 / physiology*
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Interleukin-2 Receptor alpha Subunit / deficiency
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Interleukin-2 Receptor alpha Subunit / genetics
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Membrane Proteins / deficiency
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Membrane Proteins / genetics
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Mice, Transgenic
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Proto-Oncogene Proteins / deficiency
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Proto-Oncogene Proteins / genetics
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / metabolism*
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T-Lymphocytes, Regulatory / pathology
Substances
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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IL2 protein, human
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Interleukin-2
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Interleukin-2 Receptor alpha Subunit
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Membrane Proteins
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Proto-Oncogene Proteins