Abstract
CD4(+)Foxp3(+) regulatory T (Treg) cells originate primarily from thymic differentiation, but conversion of mature T lymphocytes to Foxp3 positivity can be elicited by several means, including in vitro activation in the presence of TGF-beta. Retinoic acid (RA) increases TGF-beta-induced expression of Foxp3, through unknown molecular mechanisms. We showed here that, rather than enhancing TGF-beta signaling directly in naive CD4(+) T cells, RA negatively regulated an accompanying population of CD4(+) T cells with a CD44(hi) memory and effector phenotype. These memory cells actively inhibited the TGF-beta-induced conversion of naive CD4(+) T cells through the synthesis of a set of cytokines (IL-4, IL-21, IFN-gamma) whose expression was coordinately curtailed by RA. This indirect effect was evident in vivo and required the expression of the RA receptor alpha. Thus, cytokine-producing CD44(hi) cells actively restrain TGF-beta-mediated Foxp3 expression in naive T cells, and this balance can be shifted or fine-tuned by RA.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Forkhead Transcription Factors / immunology
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Forkhead Transcription Factors / metabolism*
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Gene Expression Regulation
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Gene Knockdown Techniques
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Homeostasis
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Hyaluronan Receptors / analysis
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Interferon-gamma / immunology
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Interferon-gamma / metabolism
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Interleukin-4 / immunology
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Interleukin-4 / metabolism
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Interleukins / immunology
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Interleukins / metabolism
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Mice
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Mice, Inbred C57BL
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Receptors, Retinoic Acid / deficiency
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Receptors, Retinoic Acid / immunology*
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Receptors, Retinoic Acid / metabolism
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Retinoic Acid Receptor alpha
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Signal Transduction
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / metabolism
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Transforming Growth Factor beta / immunology
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Transforming Growth Factor beta / metabolism
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Tretinoin / metabolism*
Substances
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Hyaluronan Receptors
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Interleukins
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Rara protein, mouse
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Receptors, Retinoic Acid
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Retinoic Acid Receptor alpha
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Transforming Growth Factor beta
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Interleukin-4
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Tretinoin
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Interferon-gamma
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interleukin-21