Abstract
Apoptosis has an essential role in controlling T cell homeostasis, especially during the contraction phase of an immune response. However, its contribution to the balance between effector and regulatory populations remains unclear. We found that Rag1(-/-) hosts repopulated with Bim(-/-) conventional CD4(+) T cells (Tconv) resulted in a larger induced regulatory T cell (iTreg) population than mice given wild-type (WT) Tconv. This appears to be due to an increased survival advantage of iTregs compared with activated Tconv in the absence of Bim. Downregulation of Bcl-2 expression and upregulation of Bim expression were more dramatic in WT iTregs than activated Tconv in the absence of IL-2 in vitro. The iTregs generated following Tconv reconstitution of Rag1(-/-) hosts exhibited lower Bcl-2 expression and higher Bim/Bcl-2 ratio than Tconv, which indicates that iTregs were in an apoptosis-prone state in vivo. A significant proportion of the peripheral iTreg pool exhibits low Bcl-2 expression indicating increased sensitivity to apoptosis, which may be a general characteristic of certain Treg subpopulations. In summary, our data suggest that iTregs and Tconv differ in their sensitivity to apoptotic stimuli due to their altered ratio of Bim/Bcl-2 expression. Modulating the apoptosis pathway may provide novel therapeutic approaches to alter the balance between effector T cells and Tregs.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Animals
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Apoptosis
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Apoptosis Regulatory Proteins / deficiency
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / immunology*
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Bcl-2-Like Protein 11
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CD4 Antigens / immunology
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Enzyme-Linked Immunosorbent Assay
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / immunology
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Gene Expression Regulation
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Homeodomain Proteins / genetics
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Homeodomain Proteins / immunology
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Homeostasis
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Inflammatory Bowel Diseases / immunology*
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Inflammatory Bowel Diseases / pathology
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Interleukin-2 / immunology
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Intestines / immunology*
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Intestines / pathology
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Lymphocyte Activation
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Membrane Proteins / deficiency
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Membrane Proteins / genetics
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Membrane Proteins / immunology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Proto-Oncogene Proteins / deficiency
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / immunology*
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / immunology*
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Signal Transduction
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Spleen / cytology
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Spleen / immunology
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T-Lymphocytes, Regulatory / cytology
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T-Lymphocytes, Regulatory / immunology*
Substances
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Apoptosis Regulatory Proteins
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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CD4 Antigens
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Homeodomain Proteins
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Interleukin-2
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Membrane Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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RAG-1 protein