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The retinoic acid-metabolizing enzyme Cyp26b1 regulates CD4 T cell differentiation and function.

Chenery A, Burrows K, Antignano F, Underhill TM, Petkovich M, Zaph C - PLoS ONE (2013)

Bottom Line: We examined the role of Cyp26b1, the T cell-specific family member, in CD4(+) T cells.Transfer of naïve Cyp26b1 (-/-) CD4(+) T cells into Rag1 (-/-) mice resulted in significantly reduced disease in a model of T cell-dependent colitis.Our results show that T cell-specific expression of Cyp26b1 is required for the development of T cell-mediated colitis and may be applicable to the development of therapeutics that target Cyp26b1 for the treatment of inflammatory bowel disease.

View Article: PubMed Central - PubMed

Affiliation: The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.

ABSTRACT
The vitamin A metabolite retinoic acid (RA) has potent immunomodulatory properties that affect T cell differentiation, migration and function. However, the precise role of RA metabolism in T cells remains unclear. Catabolism of RA is mediated by the Cyp26 family of cytochrome P450 oxidases. We examined the role of Cyp26b1, the T cell-specific family member, in CD4(+) T cells. Mice with a conditional knockout of Cyp26b1 in T cells (Cyp26b1 (-/-) mice) displayed normal lymphoid development but showed an increased sensitivity to serum retinoids, which led to increased differentiation under both inducible regulatory T (iTreg) cell- and TH17 cell-polarizing conditions in vitro. Further, Cyp26b1 expression was differentially regulated in iTreg and TH17 cells. Transfer of naïve Cyp26b1 (-/-) CD4(+) T cells into Rag1 (-/-) mice resulted in significantly reduced disease in a model of T cell-dependent colitis. Our results show that T cell-specific expression of Cyp26b1 is required for the development of T cell-mediated colitis and may be applicable to the development of therapeutics that target Cyp26b1 for the treatment of inflammatory bowel disease.

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Related in: MedlinePlus

Cyp26b1 is dispensable for normal lymphoid development.Cyp26b1 was specifically deleted in T cells. Thymus, spleen and mesenteric lymph nodes (mesLNs) from Cyp26b1fl/fl and Cyp26b1−/− mice were analyzed for CD4+ and CD8+ cell frequencies by flow cytometry. Data are from one representative experiment of 2 independent experiments (n = 3–4 per experiment).
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pone-0072308-g001: Cyp26b1 is dispensable for normal lymphoid development.Cyp26b1 was specifically deleted in T cells. Thymus, spleen and mesenteric lymph nodes (mesLNs) from Cyp26b1fl/fl and Cyp26b1−/− mice were analyzed for CD4+ and CD8+ cell frequencies by flow cytometry. Data are from one representative experiment of 2 independent experiments (n = 3–4 per experiment).

Mentions: Mice with a germline deletion of Cyp26b1 display severe bone and limb abnormalities and die in utero[14]. In order to assess the role of Cyp26b1 in adult T cells, we generated mice with a T cell-specific deletion of Cyp26b1 by breeding Cyp26b1fl/fl mice with mice expressing the Cre recombinase under the control of the Cd4 promoter/enhancer (here termed Cyp26b1−/− mice). Cyp26b1−/− mice developed normally into adult-hood, displayed no gross defects and were born with expected Mendelian ratios compared to Cyp26b1fl/fl littermates. We failed to observe any differences in the frequency of CD4+ and CD8+ single-positive, or CD4+CD8+ double-positive thymocytes in Cyp26b1−/− mice (Figure 1). Further, Cyp26b1−/− mice had equivalent frequencies of CD4+ and CD8+ cells in the spleen and mesenteric lymph nodes (mesLN) compared to Cyp26b1fl/fl mice. Thus, Cyp26b1 is not required for naïve T cell development in the thymus or periphery.


The retinoic acid-metabolizing enzyme Cyp26b1 regulates CD4 T cell differentiation and function.

Chenery A, Burrows K, Antignano F, Underhill TM, Petkovich M, Zaph C - PLoS ONE (2013)

Cyp26b1 is dispensable for normal lymphoid development.Cyp26b1 was specifically deleted in T cells. Thymus, spleen and mesenteric lymph nodes (mesLNs) from Cyp26b1fl/fl and Cyp26b1−/− mice were analyzed for CD4+ and CD8+ cell frequencies by flow cytometry. Data are from one representative experiment of 2 independent experiments (n = 3–4 per experiment).
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3750006&req=5

pone-0072308-g001: Cyp26b1 is dispensable for normal lymphoid development.Cyp26b1 was specifically deleted in T cells. Thymus, spleen and mesenteric lymph nodes (mesLNs) from Cyp26b1fl/fl and Cyp26b1−/− mice were analyzed for CD4+ and CD8+ cell frequencies by flow cytometry. Data are from one representative experiment of 2 independent experiments (n = 3–4 per experiment).
Mentions: Mice with a germline deletion of Cyp26b1 display severe bone and limb abnormalities and die in utero[14]. In order to assess the role of Cyp26b1 in adult T cells, we generated mice with a T cell-specific deletion of Cyp26b1 by breeding Cyp26b1fl/fl mice with mice expressing the Cre recombinase under the control of the Cd4 promoter/enhancer (here termed Cyp26b1−/− mice). Cyp26b1−/− mice developed normally into adult-hood, displayed no gross defects and were born with expected Mendelian ratios compared to Cyp26b1fl/fl littermates. We failed to observe any differences in the frequency of CD4+ and CD8+ single-positive, or CD4+CD8+ double-positive thymocytes in Cyp26b1−/− mice (Figure 1). Further, Cyp26b1−/− mice had equivalent frequencies of CD4+ and CD8+ cells in the spleen and mesenteric lymph nodes (mesLN) compared to Cyp26b1fl/fl mice. Thus, Cyp26b1 is not required for naïve T cell development in the thymus or periphery.

Bottom Line: We examined the role of Cyp26b1, the T cell-specific family member, in CD4(+) T cells.Transfer of naïve Cyp26b1 (-/-) CD4(+) T cells into Rag1 (-/-) mice resulted in significantly reduced disease in a model of T cell-dependent colitis.Our results show that T cell-specific expression of Cyp26b1 is required for the development of T cell-mediated colitis and may be applicable to the development of therapeutics that target Cyp26b1 for the treatment of inflammatory bowel disease.

View Article: PubMed Central - PubMed

Affiliation: The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.

ABSTRACT
The vitamin A metabolite retinoic acid (RA) has potent immunomodulatory properties that affect T cell differentiation, migration and function. However, the precise role of RA metabolism in T cells remains unclear. Catabolism of RA is mediated by the Cyp26 family of cytochrome P450 oxidases. We examined the role of Cyp26b1, the T cell-specific family member, in CD4(+) T cells. Mice with a conditional knockout of Cyp26b1 in T cells (Cyp26b1 (-/-) mice) displayed normal lymphoid development but showed an increased sensitivity to serum retinoids, which led to increased differentiation under both inducible regulatory T (iTreg) cell- and TH17 cell-polarizing conditions in vitro. Further, Cyp26b1 expression was differentially regulated in iTreg and TH17 cells. Transfer of naïve Cyp26b1 (-/-) CD4(+) T cells into Rag1 (-/-) mice resulted in significantly reduced disease in a model of T cell-dependent colitis. Our results show that T cell-specific expression of Cyp26b1 is required for the development of T cell-mediated colitis and may be applicable to the development of therapeutics that target Cyp26b1 for the treatment of inflammatory bowel disease.

Show MeSH
Related in: MedlinePlus