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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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Wnt signaling components expression in wild type and PGRN-deficient CD4+CD25+ T cells measured by real-time PCR.All values are shown as a relative ratio to GAPDH measured by 2-ΔΔct method. Data represent as a means ±SE of a representative experiment. *p<0.05; **p<0.01.
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pone-0112110-g008: Wnt signaling components expression in wild type and PGRN-deficient CD4+CD25+ T cells measured by real-time PCR.All values are shown as a relative ratio to GAPDH measured by 2-ΔΔct method. Data represent as a means ±SE of a representative experiment. *p<0.05; **p<0.01.

Mentions: Wnt signaling proteins can be divided into two subgroups according to the downstream molecules, the canonical pathway which stabilized β-catenin and activated target genes through the regulation of TCF/Lef transcription factors, and the noncanonical pathway did not dependent on the regulation of β-catenin and activated protein kinase C and G proteins, etc [38]. It was reported that Wnt signaling regulated PGRN-mediated frontotemporal dementia (FTD) and PGRN and Wnt reciprocally regulated each other [38], [39]. Moreover, Wnt signaling was also reported to stabilize the survival of CD4+CD25+ Treg cells and to enhance their suppressive capacity [9], [40]. To further study the molecular events underlying PGRN-mediated regulation of CD4+CD25+ T cells, we purified CD4+CD25+ T cells from splenocytes of wild type and PGRN-deficient mice by FACS sorting and examined the gene expression of Wnt signaling components through real-time PCR. Our results did not found significantly change of Wnt1, Wnt2, Wnt3a, Wnt4, Wnt5a, Wnt5b, Wnt7a, Wnt8b, Wnt11, Wisp2, Fzd1, Fzd4, Fzd6, Fzd7, Fzd8, Fzd9, Fzd10, β-catenin, TCF1, TCF3, wisp1 and axin2 gene expression (p>0.05) (Fig. 8). Interestingly, the mRNA level of Fzd2 gene in PGRN-deficient CD4+CD25+ T cells was significantly upregulated, when compared with its expression in wild type CD4+CD25+ T cells (p<0.01) (Fig. 8). Collectively, this set of experiments indicated that PGRN deficiency upregulates the expression of Fzd2 gene in CD4+CD25+ T cells.


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)

Wnt signaling components expression in wild type and PGRN-deficient CD4+CD25+ T cells measured by real-time PCR.All values are shown as a relative ratio to GAPDH measured by 2-ΔΔct method. Data represent as a means ±SE of a representative experiment. *p<0.05; **p<0.01.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0112110-g008: Wnt signaling components expression in wild type and PGRN-deficient CD4+CD25+ T cells measured by real-time PCR.All values are shown as a relative ratio to GAPDH measured by 2-ΔΔct method. Data represent as a means ±SE of a representative experiment. *p<0.05; **p<0.01.
Mentions: Wnt signaling proteins can be divided into two subgroups according to the downstream molecules, the canonical pathway which stabilized β-catenin and activated target genes through the regulation of TCF/Lef transcription factors, and the noncanonical pathway did not dependent on the regulation of β-catenin and activated protein kinase C and G proteins, etc [38]. It was reported that Wnt signaling regulated PGRN-mediated frontotemporal dementia (FTD) and PGRN and Wnt reciprocally regulated each other [38], [39]. Moreover, Wnt signaling was also reported to stabilize the survival of CD4+CD25+ Treg cells and to enhance their suppressive capacity [9], [40]. To further study the molecular events underlying PGRN-mediated regulation of CD4+CD25+ T cells, we purified CD4+CD25+ T cells from splenocytes of wild type and PGRN-deficient mice by FACS sorting and examined the gene expression of Wnt signaling components through real-time PCR. Our results did not found significantly change of Wnt1, Wnt2, Wnt3a, Wnt4, Wnt5a, Wnt5b, Wnt7a, Wnt8b, Wnt11, Wisp2, Fzd1, Fzd4, Fzd6, Fzd7, Fzd8, Fzd9, Fzd10, β-catenin, TCF1, TCF3, wisp1 and axin2 gene expression (p>0.05) (Fig. 8). Interestingly, the mRNA level of Fzd2 gene in PGRN-deficient CD4+CD25+ T cells was significantly upregulated, when compared with its expression in wild type CD4+CD25+ T cells (p<0.01) (Fig. 8). Collectively, this set of experiments indicated that PGRN deficiency upregulates the expression of Fzd2 gene in CD4+CD25+ T cells.

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