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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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PGRN deficiency does not affect the conversion of naïve CD4+CD25- T cells into iTreg mediated by TGF-β.Naïve CD4+ CD25- T cells isolated from both wildtype (WT) and PGRN-deficient mice were stimulated with plate-bound CD3 Ab and solute CD28 Ab and cultured the cells for 3-4 days in the presence or absence of TGF-β, and the expression of GFP was measured by FACS. (A) The GFP levels in CD4+ T cells in the absence of TGF-β. (B) The GFP levels in CD4+ T cells in the presence of 1 ng/ml TGF-β. (C) The GFP levels in CD4+ T cells in the presence of 10 ng/ml TGF-β. All data were repeated three times with similar results.
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pone-0112110-g003: PGRN deficiency does not affect the conversion of naïve CD4+CD25- T cells into iTreg mediated by TGF-β.Naïve CD4+ CD25- T cells isolated from both wildtype (WT) and PGRN-deficient mice were stimulated with plate-bound CD3 Ab and solute CD28 Ab and cultured the cells for 3-4 days in the presence or absence of TGF-β, and the expression of GFP was measured by FACS. (A) The GFP levels in CD4+ T cells in the absence of TGF-β. (B) The GFP levels in CD4+ T cells in the presence of 1 ng/ml TGF-β. (C) The GFP levels in CD4+ T cells in the presence of 10 ng/ml TGF-β. All data were repeated three times with similar results.

Mentions: Since iTreg cells are essential in immune tolerance and in the prevention of chronic inflammation [34], growth factors which can boost TGF-β-mediated the conversion of CD4+CD25- T cells into iTreg will be of great importance in inflammatory conditions. TGF-β was reported to induce Foxp3-expressing iTreg [35]. We sought to determine whether PGRN regulates the conversion of CD4+CD25- T cells into iTreg. In a loss-of-function study, we first stimulated naïve wild type and PGRN-deficient CD4+CD25- T cells with plate-bound CD3 antibody and soluble CD28 antibody in the presence of IL-2 and cultured for 3-4 days with or without TGF-β. In the absence of TGF-β, PGRN-deficient CD4+CD25- T cells have comparable capacity to convert into iTreg cells (0.10±0.02% Foxp3+ cells in KO versus 0.12±0.01% in WT, p>0.05) (Fig. 3A). In addition, no difference were found in wild type and PGRN-deficient CD4+CD25- T cells conversion into iTreg cells in the presence of TGF-β at dose of 1 ng/ml (49.8±3.3% Foxp3+ cells in KO versus 48.3±1.0% in WT, p>0.05) and 10 ng/ml (84±1.4% Foxp3+ cells in KO versus 84.3±3.5% in WT, p>0.05) (Fig. 3B-C). Thus, the findings suggest endogenous PGRN may not be required for CD4+CD25- T cells conversion into iTreg.


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)

PGRN deficiency does not affect the conversion of naïve CD4+CD25- T cells into iTreg mediated by TGF-β.Naïve CD4+ CD25- T cells isolated from both wildtype (WT) and PGRN-deficient mice were stimulated with plate-bound CD3 Ab and solute CD28 Ab and cultured the cells for 3-4 days in the presence or absence of TGF-β, and the expression of GFP was measured by FACS. (A) The GFP levels in CD4+ T cells in the absence of TGF-β. (B) The GFP levels in CD4+ T cells in the presence of 1 ng/ml TGF-β. (C) The GFP levels in CD4+ T cells in the presence of 10 ng/ml TGF-β. All data were repeated three times with similar results.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0112110-g003: PGRN deficiency does not affect the conversion of naïve CD4+CD25- T cells into iTreg mediated by TGF-β.Naïve CD4+ CD25- T cells isolated from both wildtype (WT) and PGRN-deficient mice were stimulated with plate-bound CD3 Ab and solute CD28 Ab and cultured the cells for 3-4 days in the presence or absence of TGF-β, and the expression of GFP was measured by FACS. (A) The GFP levels in CD4+ T cells in the absence of TGF-β. (B) The GFP levels in CD4+ T cells in the presence of 1 ng/ml TGF-β. (C) The GFP levels in CD4+ T cells in the presence of 10 ng/ml TGF-β. All data were repeated three times with similar results.
Mentions: Since iTreg cells are essential in immune tolerance and in the prevention of chronic inflammation [34], growth factors which can boost TGF-β-mediated the conversion of CD4+CD25- T cells into iTreg will be of great importance in inflammatory conditions. TGF-β was reported to induce Foxp3-expressing iTreg [35]. We sought to determine whether PGRN regulates the conversion of CD4+CD25- T cells into iTreg. In a loss-of-function study, we first stimulated naïve wild type and PGRN-deficient CD4+CD25- T cells with plate-bound CD3 antibody and soluble CD28 antibody in the presence of IL-2 and cultured for 3-4 days with or without TGF-β. In the absence of TGF-β, PGRN-deficient CD4+CD25- T cells have comparable capacity to convert into iTreg cells (0.10±0.02% Foxp3+ cells in KO versus 0.12±0.01% in WT, p>0.05) (Fig. 3A). In addition, no difference were found in wild type and PGRN-deficient CD4+CD25- T cells conversion into iTreg cells in the presence of TGF-β at dose of 1 ng/ml (49.8±3.3% Foxp3+ cells in KO versus 48.3±1.0% in WT, p>0.05) and 10 ng/ml (84±1.4% Foxp3+ cells in KO versus 84.3±3.5% in WT, p>0.05) (Fig. 3B-C). Thus, the findings suggest endogenous PGRN may not be required for CD4+CD25- T cells conversion into iTreg.

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