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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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Cyp26b1 is not required for nTreg cell development and suppressive function.T cells were isolated from spleens of Cyp26b1fl/fl and Cyp26b1−/− mice. (A) CD4+Foxp3+CD25+ nTreg cell frequencies were determined by flow cytometry. (B) Purified CD4+CD25+ nTreg were co-cultured with CFSE-labeled CD4+CD25− conventional T (Tc) cells at increasing ratios and suppression of Tc cells was measured by flow cytometry. Data in (A) are from one representative experiment of 3 independent experiments (n = 3−4 per experiment); Data in (B) are from a single experiment.
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pone-0072308-g002: Cyp26b1 is not required for nTreg cell development and suppressive function.T cells were isolated from spleens of Cyp26b1fl/fl and Cyp26b1−/− mice. (A) CD4+Foxp3+CD25+ nTreg cell frequencies were determined by flow cytometry. (B) Purified CD4+CD25+ nTreg were co-cultured with CFSE-labeled CD4+CD25− conventional T (Tc) cells at increasing ratios and suppression of Tc cells was measured by flow cytometry. Data in (A) are from one representative experiment of 3 independent experiments (n = 3−4 per experiment); Data in (B) are from a single experiment.

Mentions: The role of RA signaling in the development of thymic-derived naturally-occurring Treg (nTreg) cell development has not been examined in detail, although RAR-activating retinoids have been shown to be produced within the thymus [15]. We examined the frequency and function of nTreg cells in Cyp26b1−/− mice. We observed equivalent frequencies of nTreg cells in the spleens of Cyp26b1fl/fl and Cyp26b1−/− mice (Figure 2A), suggesting that RA signaling is not a major determinant of nTreg cell development. Further, Cyp26b1 was dispensable for the suppressive ability of nTreg cells (Figure 2B), as nTreg cells from either Cyp26b1fl/fl or Cyp26b1−/− mice were able to suppress effector T cell proliferation equivalently. Thus, Cyp26b1-dependent RA metabolism is not required for nTreg cell development and suppressive function.


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 not required for nTreg cell development and suppressive function.T cells were isolated from spleens of Cyp26b1fl/fl and Cyp26b1−/− mice. (A) CD4+Foxp3+CD25+ nTreg cell frequencies were determined by flow cytometry. (B) Purified CD4+CD25+ nTreg were co-cultured with CFSE-labeled CD4+CD25− conventional T (Tc) cells at increasing ratios and suppression of Tc cells was measured by flow cytometry. Data in (A) are from one representative experiment of 3 independent experiments (n = 3−4 per experiment); Data in (B) are from a single experiment.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0072308-g002: Cyp26b1 is not required for nTreg cell development and suppressive function.T cells were isolated from spleens of Cyp26b1fl/fl and Cyp26b1−/− mice. (A) CD4+Foxp3+CD25+ nTreg cell frequencies were determined by flow cytometry. (B) Purified CD4+CD25+ nTreg were co-cultured with CFSE-labeled CD4+CD25− conventional T (Tc) cells at increasing ratios and suppression of Tc cells was measured by flow cytometry. Data in (A) are from one representative experiment of 3 independent experiments (n = 3−4 per experiment); Data in (B) are from a single experiment.
Mentions: The role of RA signaling in the development of thymic-derived naturally-occurring Treg (nTreg) cell development has not been examined in detail, although RAR-activating retinoids have been shown to be produced within the thymus [15]. We examined the frequency and function of nTreg cells in Cyp26b1−/− mice. We observed equivalent frequencies of nTreg cells in the spleens of Cyp26b1fl/fl and Cyp26b1−/− mice (Figure 2A), suggesting that RA signaling is not a major determinant of nTreg cell development. Further, Cyp26b1 was dispensable for the suppressive ability of nTreg cells (Figure 2B), as nTreg cells from either Cyp26b1fl/fl or Cyp26b1−/− mice were able to suppress effector T cell proliferation equivalently. Thus, Cyp26b1-dependent RA metabolism is not required for nTreg cell development and suppressive function.

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