Abstract
E3 ubiquitin ligase Casitas-B-lineage lymphoma protein-b (Cbl-b) is critical for establishing the threshold for T cell activation and is essential for induction of T cell anergy. Recent studies suggest that Cbl-b is involved in the development of CD4(+)CD25(+) inducible regulatory T cells (iTregs). In this study, we report that the optimal induction of Foxp3 by naive CD4(+)CD25(-) T cells requires suboptimal TCR triggering. In the absence of Cbl-b, the TCR strength for optimal Foxp3 induction is downregulated in vitro. Using TCR-transgenic Rag(-/-) mice in combination with Cbl-b deficiency, we show that in vivo iTreg development is also controlled by Cbl-b via tuning the TCR strength. Furthermore, we show that Akt-2 but not Akt-1 regulates Foxp3 expression downstream of Cbl-b. Therefore, we demonstrate that Cbl-b regulates the fate of iTregs via controlling the threshold for T cell activation.
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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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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CD4 Antigens / metabolism
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Cell Differentiation / immunology
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Cells, Cultured
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Down-Regulation
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Forkhead Transcription Factors / metabolism
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Homeodomain Proteins / genetics
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Interleukin-2 Receptor alpha Subunit / metabolism
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Lymphocyte Activation*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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NF-kappa B / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-cbl / metabolism*
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T-Lymphocytes, Regulatory / immunology*
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Ubiquitin-Protein Ligases / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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CD4 Antigens
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Cblb protein, mouse
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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 Receptor alpha Subunit
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NF-kappa B
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RAG-1 protein
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Proto-Oncogene Proteins c-cbl
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Ubiquitin-Protein Ligases
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Akt1 protein, mouse
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Akt2 protein, mouse
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Proto-Oncogene Proteins c-akt