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Progranulin facilitates conversion and function of regulatory T cells under inflammatory conditions.

Wei F, Zhang Y, Zhao W, Yu X, Liu CJ - PLoS ONE (2014)

Bottom Line: PGRN was required for the immunosuppressive function of Tregs, since PGRN-deficient Tregs have a significant decreased ability to suppress the proliferation of effector T cells (Teff).In addition, PGRN deficiency caused a marked reduction in Tregs number in the course of inflammatory arthritis, although no significant difference was observed in the numbers of Tregs between wild type and PGRN deficient mice during development.Furthermore, PGRN deficiency led to significant upregulation of the Wnt receptor gene Fzd2.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopaedic Surgery, New York University Medical Center, New York, New York, United States of America; Institute of Pathogenic Biology, Shandong University School of Medicine, Jinan, China.

ABSTRACT
The progranulin (PGRN) is known to protect regulatory T cells (Tregs) from a negative regulation by TNF-α, and its levels are elevated in various kinds of autoimmune diseases. Whether PGRN directly regulates the conversion of CD4+CD25-T cells into Foxp3-expressing regulatory T cells (iTreg), and whether PGRN affects the immunosuppressive function of Tregs, however, remain unknown. In this study we provide evidences demonstrating that PGRN is able to stimulate the conversion of CD4+CD25-T cells into iTreg in a dose-dependent manner in vitro. In addition, PGRN showed synergistic effects with TGF-β1 on the induction of iTreg. PGRN was required for the immunosuppressive function of Tregs, since PGRN-deficient Tregs have a significant decreased ability to suppress the proliferation of effector T cells (Teff). In addition, PGRN deficiency caused a marked reduction in Tregs number in the course of inflammatory arthritis, although no significant difference was observed in the numbers of Tregs between wild type and PGRN deficient mice during development. Furthermore, PGRN deficiency led to significant upregulation of the Wnt receptor gene Fzd2. Collectively, this study reveals that PGRN directly regulates the numbers and function of Tregs under inflammatory conditions, and provides new insight into the immune regulatory mechanism of PGRN in the pathogenesis of inflammatory and immune-related diseases.

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In vivo proliferation of CD4+CD25+ T cells from spleen and lymph nodes analyzed by BrdU corporation.Wild type and PGRN-deficient mice were injected intraperitoneally with BrdU labeling reagents, and the degrees of BrdU incorporation by CD4+CD25+ T cells from lymphocytes of spleen and lymph nodes were determined by FACS. (A) The BrdU incorporation of wild type CD4+CD25+ T cells from splenocytes. (B) The BrdU incorporation of PGRN-deficient CD4+CD25+ T cells from splenocytes. (C) The percentage of wild type CD4+CD25+ T cells from lymphocytes of lymph nodes that incorporated BrdU. (D) The percentage of PGRN-deficient CD4+CD25+ T cells from lymphocytes of lymph nodes that incorporated BrdU. All data was representative of three mice per group and indicated as mean ±SEM.
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pone-0112110-g006: In vivo proliferation of CD4+CD25+ T cells from spleen and lymph nodes analyzed by BrdU corporation.Wild type and PGRN-deficient mice were injected intraperitoneally with BrdU labeling reagents, and the degrees of BrdU incorporation by CD4+CD25+ T cells from lymphocytes of spleen and lymph nodes were determined by FACS. (A) The BrdU incorporation of wild type CD4+CD25+ T cells from splenocytes. (B) The BrdU incorporation of PGRN-deficient CD4+CD25+ T cells from splenocytes. (C) The percentage of wild type CD4+CD25+ T cells from lymphocytes of lymph nodes that incorporated BrdU. (D) The percentage of PGRN-deficient CD4+CD25+ T cells from lymphocytes of lymph nodes that incorporated BrdU. All data was representative of three mice per group and indicated as mean ±SEM.

Mentions: 5-Bromo-2-deoxyuridine (BrdU) is a pyrimidine analogue of thymidine, selectively incorporated into replicating DNA, effectively tagging dividing cells. To determine whether PGRN deficiency alters the proliferation of Tregs in vivo, we set a BrdU incorporation assay. We injected BrdU labeling reagent (BrdU, Sigma-Aldrich) at a dose of 10 ml/kg body weight into wild type and PGRN-deficient mice, three mice per group. Mice were sacrificed 2 hours after injection and intracellular staining of BrdU in lymphocytes of spleen (SP) and lymph nodes (LN) were stained with BrdU flow kit (BD Bioscience) and analyzed by FACS. We did not observe any significant changes in the number of CD4+CD25+BrdU+ cells from splenocytes between wild-type and PGRN-deficient mice (6.58±1.42% BrdU+ cells in KO versus 5.68±0.11% BrdU+ cells in WT, p>0.05) (Fig. 6A–B). In addition, 6.54±1.46% of the cells in lymphocytes of lymph nodes are BrdU positive from PGRN-deficient mice, and comparable to 6.58±0.77% BrdU+ cells seen in wild type mice (p>0.05) (Fig. 6C and D). These findings suggest that wild type and PGRN-deficient CD4+CD25+ Treg cells have a comparable proliferation and division capacity in vivo.


Progranulin facilitates conversion and function of regulatory T cells under inflammatory conditions.

Wei F, Zhang Y, Zhao W, Yu X, Liu CJ - PLoS ONE (2014)

In vivo proliferation of CD4+CD25+ T cells from spleen and lymph nodes analyzed by BrdU corporation.Wild type and PGRN-deficient mice were injected intraperitoneally with BrdU labeling reagents, and the degrees of BrdU incorporation by CD4+CD25+ T cells from lymphocytes of spleen and lymph nodes were determined by FACS. (A) The BrdU incorporation of wild type CD4+CD25+ T cells from splenocytes. (B) The BrdU incorporation of PGRN-deficient CD4+CD25+ T cells from splenocytes. (C) The percentage of wild type CD4+CD25+ T cells from lymphocytes of lymph nodes that incorporated BrdU. (D) The percentage of PGRN-deficient CD4+CD25+ T cells from lymphocytes of lymph nodes that incorporated BrdU. All data was representative of three mice per group and indicated as mean ±SEM.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230946&req=5

pone-0112110-g006: In vivo proliferation of CD4+CD25+ T cells from spleen and lymph nodes analyzed by BrdU corporation.Wild type and PGRN-deficient mice were injected intraperitoneally with BrdU labeling reagents, and the degrees of BrdU incorporation by CD4+CD25+ T cells from lymphocytes of spleen and lymph nodes were determined by FACS. (A) The BrdU incorporation of wild type CD4+CD25+ T cells from splenocytes. (B) The BrdU incorporation of PGRN-deficient CD4+CD25+ T cells from splenocytes. (C) The percentage of wild type CD4+CD25+ T cells from lymphocytes of lymph nodes that incorporated BrdU. (D) The percentage of PGRN-deficient CD4+CD25+ T cells from lymphocytes of lymph nodes that incorporated BrdU. All data was representative of three mice per group and indicated as mean ±SEM.
Mentions: 5-Bromo-2-deoxyuridine (BrdU) is a pyrimidine analogue of thymidine, selectively incorporated into replicating DNA, effectively tagging dividing cells. To determine whether PGRN deficiency alters the proliferation of Tregs in vivo, we set a BrdU incorporation assay. We injected BrdU labeling reagent (BrdU, Sigma-Aldrich) at a dose of 10 ml/kg body weight into wild type and PGRN-deficient mice, three mice per group. Mice were sacrificed 2 hours after injection and intracellular staining of BrdU in lymphocytes of spleen (SP) and lymph nodes (LN) were stained with BrdU flow kit (BD Bioscience) and analyzed by FACS. We did not observe any significant changes in the number of CD4+CD25+BrdU+ cells from splenocytes between wild-type and PGRN-deficient mice (6.58±1.42% BrdU+ cells in KO versus 5.68±0.11% BrdU+ cells in WT, p>0.05) (Fig. 6A–B). In addition, 6.54±1.46% of the cells in lymphocytes of lymph nodes are BrdU positive from PGRN-deficient mice, and comparable to 6.58±0.77% BrdU+ cells seen in wild type mice (p>0.05) (Fig. 6C and D). These findings suggest that wild type and PGRN-deficient CD4+CD25+ Treg cells have a comparable proliferation and division capacity in vivo.

Bottom Line: PGRN was required for the immunosuppressive function of Tregs, since PGRN-deficient Tregs have a significant decreased ability to suppress the proliferation of effector T cells (Teff).In addition, PGRN deficiency caused a marked reduction in Tregs number in the course of inflammatory arthritis, although no significant difference was observed in the numbers of Tregs between wild type and PGRN deficient mice during development.Furthermore, PGRN deficiency led to significant upregulation of the Wnt receptor gene Fzd2.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopaedic Surgery, New York University Medical Center, New York, New York, United States of America; Institute of Pathogenic Biology, Shandong University School of Medicine, Jinan, China.

ABSTRACT
The progranulin (PGRN) is known to protect regulatory T cells (Tregs) from a negative regulation by TNF-α, and its levels are elevated in various kinds of autoimmune diseases. Whether PGRN directly regulates the conversion of CD4+CD25-T cells into Foxp3-expressing regulatory T cells (iTreg), and whether PGRN affects the immunosuppressive function of Tregs, however, remain unknown. In this study we provide evidences demonstrating that PGRN is able to stimulate the conversion of CD4+CD25-T cells into iTreg in a dose-dependent manner in vitro. In addition, PGRN showed synergistic effects with TGF-β1 on the induction of iTreg. PGRN was required for the immunosuppressive function of Tregs, since PGRN-deficient Tregs have a significant decreased ability to suppress the proliferation of effector T cells (Teff). In addition, PGRN deficiency caused a marked reduction in Tregs number in the course of inflammatory arthritis, although no significant difference was observed in the numbers of Tregs between wild type and PGRN deficient mice during development. Furthermore, PGRN deficiency led to significant upregulation of the Wnt receptor gene Fzd2. Collectively, this study reveals that PGRN directly regulates the numbers and function of Tregs under inflammatory conditions, and provides new insight into the immune regulatory mechanism of PGRN in the pathogenesis of inflammatory and immune-related diseases.

Show MeSH
Related in: MedlinePlus