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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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Fewer CD4+CD25+Foxp3+ Treg cells seen in PGRN-deficient CIA model.Wild type (n = 6) and PGRN-deficient mice (n = 6) were intradermally immunized with 100 µl of chicken type II collagen emulsified with an equal volume of complete Freund's adjuvant (CFA). 21 days post immunization, draining lymph nodes were extracted and CD4+CD25+Foxp3+ T cells were analyzed by FACS. Data represent as a means ±SE of a representative experiment. **p<0.01.
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pone-0112110-g007: Fewer CD4+CD25+Foxp3+ Treg cells seen in PGRN-deficient CIA model.Wild type (n = 6) and PGRN-deficient mice (n = 6) were intradermally immunized with 100 µl of chicken type II collagen emulsified with an equal volume of complete Freund's adjuvant (CFA). 21 days post immunization, draining lymph nodes were extracted and CD4+CD25+Foxp3+ T cells were analyzed by FACS. Data represent as a means ±SE of a representative experiment. **p<0.01.

Mentions: To determine whether the PGRN deficiency alters the number of Tregs in inflammatory conditions, we established a collagen-induced arthritis (CIA) model. Wild type and PGRN-deficient mice, six mice per group, were intradermally injected with 100 µl of the emulsion at the base of the tail. Two group mice were sacrificed 21 days after immunization and intracellular staining of Foxp3 in lymphocytes of draining lymph nodes (LN) was stained and analyzed by FACS. The results demonstrate that PGRN-deficient CD4+CD25- T cells have an impaired ability to generate iTreg in arthritis conditions (Fig. 7A–B). Arthritic PGRN-deficient mice shown a significant changes in the number of CD4+CD25+Foxp3+ cells from draining lymph nodes (11.8±0.2% CD4+CD25+Foxp3+ cells in arthritic KO mice versus 20.4±2.7% CD4+CD25+Foxp3+ cells in arthritic WT mice, p<0.01, Fig. 7A–B). These findings suggest that PGRN deficiency leads to fewer CD4+CD25+Foxp3+ Treg cells in collagen-induced arthritis conditions.


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)

Fewer CD4+CD25+Foxp3+ Treg cells seen in PGRN-deficient CIA model.Wild type (n = 6) and PGRN-deficient mice (n = 6) were intradermally immunized with 100 µl of chicken type II collagen emulsified with an equal volume of complete Freund's adjuvant (CFA). 21 days post immunization, draining lymph nodes were extracted and CD4+CD25+Foxp3+ T cells were analyzed by FACS. Data represent as a means ±SE of a representative experiment. **p<0.01.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0112110-g007: Fewer CD4+CD25+Foxp3+ Treg cells seen in PGRN-deficient CIA model.Wild type (n = 6) and PGRN-deficient mice (n = 6) were intradermally immunized with 100 µl of chicken type II collagen emulsified with an equal volume of complete Freund's adjuvant (CFA). 21 days post immunization, draining lymph nodes were extracted and CD4+CD25+Foxp3+ T cells were analyzed by FACS. Data represent as a means ±SE of a representative experiment. **p<0.01.
Mentions: To determine whether the PGRN deficiency alters the number of Tregs in inflammatory conditions, we established a collagen-induced arthritis (CIA) model. Wild type and PGRN-deficient mice, six mice per group, were intradermally injected with 100 µl of the emulsion at the base of the tail. Two group mice were sacrificed 21 days after immunization and intracellular staining of Foxp3 in lymphocytes of draining lymph nodes (LN) was stained and analyzed by FACS. The results demonstrate that PGRN-deficient CD4+CD25- T cells have an impaired ability to generate iTreg in arthritis conditions (Fig. 7A–B). Arthritic PGRN-deficient mice shown a significant changes in the number of CD4+CD25+Foxp3+ cells from draining lymph nodes (11.8±0.2% CD4+CD25+Foxp3+ cells in arthritic KO mice versus 20.4±2.7% CD4+CD25+Foxp3+ cells in arthritic WT mice, p<0.01, Fig. 7A–B). These findings suggest that PGRN deficiency leads to fewer CD4+CD25+Foxp3+ Treg cells in collagen-induced arthritis conditions.

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