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WASP regulates suppressor activity of human and murine CD4(+)CD25(+)FOXP3(+) natural regulatory T cells.

Marangoni F, Trifari S, Scaramuzza S, Panaroni C, Martino S, Notarangelo LD, Baz Z, Metin A, Cattaneo F, Villa A, Aiuti A, Battaglia M, Roncarolo MG, Dupré L - J. Exp. Med. (2007)

Bottom Line: Moreover, WAS(-/-) nTreg cells failed to proliferate and to produce transforming growth factor beta upon T cell receptor (TCR)/CD28 triggering.Compared with WT nTreg cells, WAS(-/-) nTreg cells showed reduced in vitro suppressor activity on both WT and WAS(-/-) effector T cells.Similarly, peripheral nTreg cells were present at normal levels in WAS patients but failed to suppress proliferation of autologous and allogeneic CD4(+) effector T cells in vitro.

View Article: PubMed Central - PubMed

Affiliation: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), 20132 Milan, Italy.

ABSTRACT
A large proportion of Wiskott-Aldrich syndrome (WAS) patients develop autoimmunity and allergy. CD4(+)CD25(+)FOXP3(+) natural regulatory T (nTreg) cells play a key role in peripheral tolerance to prevent immune responses to self-antigens and allergens. Therefore, we investigated the effect of WAS protein (WASP) deficiency on the distribution and suppressor function of nTreg cells. In WAS(-/-) mice, the steady-state distribution and phenotype of nTreg cells in the thymus and spleen were normal. However, WAS(-/-) nTreg cells engrafted poorly in immunized mice, indicating perturbed homeostasis. Moreover, WAS(-/-) nTreg cells failed to proliferate and to produce transforming growth factor beta upon T cell receptor (TCR)/CD28 triggering. WASP-dependent F-actin polarization to the site of TCR triggering might not be involved in WAS(-/-) nTreg cell defects because this process was also inefficient in wild-type (WT) nTreg cells. Compared with WT nTreg cells, WAS(-/-) nTreg cells showed reduced in vitro suppressor activity on both WT and WAS(-/-) effector T cells. Similarly, peripheral nTreg cells were present at normal levels in WAS patients but failed to suppress proliferation of autologous and allogeneic CD4(+) effector T cells in vitro. Thus, WASP appears to play an important role in the activation and suppressor function of nTreg cells, and a dysfunction or incorrect localization of nTreg cells may contribute to the development of autoimmunity in WAS patients.

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Immunophenotype of nTreg cells from human peripheral blood. (a) CD4+FOXP3+ cells in the peripheral blood of WAS patients. PBMCs from four representative HDs and seven WAS patients (WAS) were stained with anti-CD4 and anti-FOXP3 mAbs. Results shown are gated on the CD4+ T cells. Numbers indicate the percentages of FOXP3+ cells among CD4+ T cells. (b) Percentage of FOXP3+ cells (left), CD25+FOXP3+ cells (middle), and CD25− FOXP3+ cells (right) among CD4+ T cells of HDs (n = 16) and WAS patients (n = 7). Bars represent the median value for each group.
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fig6: Immunophenotype of nTreg cells from human peripheral blood. (a) CD4+FOXP3+ cells in the peripheral blood of WAS patients. PBMCs from four representative HDs and seven WAS patients (WAS) were stained with anti-CD4 and anti-FOXP3 mAbs. Results shown are gated on the CD4+ T cells. Numbers indicate the percentages of FOXP3+ cells among CD4+ T cells. (b) Percentage of FOXP3+ cells (left), CD25+FOXP3+ cells (middle), and CD25− FOXP3+ cells (right) among CD4+ T cells of HDs (n = 16) and WAS patients (n = 7). Bars represent the median value for each group.

Mentions: To our knowledge, the role of WASP in the generation and function of human nTreg cells has never been studied. As observed in murine cells, levels of WASP expression in CD4+CD25+ and CD4+CD25− T cells from the blood of healthy donors (HDs) were comparable (not depicted). To investigate the role of WASP in the generation of human nTreg cells, we analyzed CD4+CD25+FOXP3+ T cells from the peripheral blood of seven WAS patients of different ages and different clinical scores (Table I). Percentages of FOXP3+ cells among CD4+ T cells of WAS patients were either higher or comparable to those observed in HDs (Fig. 6 a). Overall analysis revealed a slight increase in FOXP3+ cells within patients' CD4+ T lymphocytes, which is mainly due to an increase in CD4+CD25+FOXP3+ T cells (Fig. 6 b). The MFI values of CD25 and FOXP3 in CD4+ T cells from WAS patients were comparable to those measured in HDs (not depicted). These results indicate that WAS patients have a normal or increased proportion of circulating nTreg cells.


WASP regulates suppressor activity of human and murine CD4(+)CD25(+)FOXP3(+) natural regulatory T cells.

Marangoni F, Trifari S, Scaramuzza S, Panaroni C, Martino S, Notarangelo LD, Baz Z, Metin A, Cattaneo F, Villa A, Aiuti A, Battaglia M, Roncarolo MG, Dupré L - J. Exp. Med. (2007)

Immunophenotype of nTreg cells from human peripheral blood. (a) CD4+FOXP3+ cells in the peripheral blood of WAS patients. PBMCs from four representative HDs and seven WAS patients (WAS) were stained with anti-CD4 and anti-FOXP3 mAbs. Results shown are gated on the CD4+ T cells. Numbers indicate the percentages of FOXP3+ cells among CD4+ T cells. (b) Percentage of FOXP3+ cells (left), CD25+FOXP3+ cells (middle), and CD25− FOXP3+ cells (right) among CD4+ T cells of HDs (n = 16) and WAS patients (n = 7). Bars represent the median value for each group.
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Related In: Results  -  Collection

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fig6: Immunophenotype of nTreg cells from human peripheral blood. (a) CD4+FOXP3+ cells in the peripheral blood of WAS patients. PBMCs from four representative HDs and seven WAS patients (WAS) were stained with anti-CD4 and anti-FOXP3 mAbs. Results shown are gated on the CD4+ T cells. Numbers indicate the percentages of FOXP3+ cells among CD4+ T cells. (b) Percentage of FOXP3+ cells (left), CD25+FOXP3+ cells (middle), and CD25− FOXP3+ cells (right) among CD4+ T cells of HDs (n = 16) and WAS patients (n = 7). Bars represent the median value for each group.
Mentions: To our knowledge, the role of WASP in the generation and function of human nTreg cells has never been studied. As observed in murine cells, levels of WASP expression in CD4+CD25+ and CD4+CD25− T cells from the blood of healthy donors (HDs) were comparable (not depicted). To investigate the role of WASP in the generation of human nTreg cells, we analyzed CD4+CD25+FOXP3+ T cells from the peripheral blood of seven WAS patients of different ages and different clinical scores (Table I). Percentages of FOXP3+ cells among CD4+ T cells of WAS patients were either higher or comparable to those observed in HDs (Fig. 6 a). Overall analysis revealed a slight increase in FOXP3+ cells within patients' CD4+ T lymphocytes, which is mainly due to an increase in CD4+CD25+FOXP3+ T cells (Fig. 6 b). The MFI values of CD25 and FOXP3 in CD4+ T cells from WAS patients were comparable to those measured in HDs (not depicted). These results indicate that WAS patients have a normal or increased proportion of circulating nTreg cells.

Bottom Line: Moreover, WAS(-/-) nTreg cells failed to proliferate and to produce transforming growth factor beta upon T cell receptor (TCR)/CD28 triggering.Compared with WT nTreg cells, WAS(-/-) nTreg cells showed reduced in vitro suppressor activity on both WT and WAS(-/-) effector T cells.Similarly, peripheral nTreg cells were present at normal levels in WAS patients but failed to suppress proliferation of autologous and allogeneic CD4(+) effector T cells in vitro.

View Article: PubMed Central - PubMed

Affiliation: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), 20132 Milan, Italy.

ABSTRACT
A large proportion of Wiskott-Aldrich syndrome (WAS) patients develop autoimmunity and allergy. CD4(+)CD25(+)FOXP3(+) natural regulatory T (nTreg) cells play a key role in peripheral tolerance to prevent immune responses to self-antigens and allergens. Therefore, we investigated the effect of WAS protein (WASP) deficiency on the distribution and suppressor function of nTreg cells. In WAS(-/-) mice, the steady-state distribution and phenotype of nTreg cells in the thymus and spleen were normal. However, WAS(-/-) nTreg cells engrafted poorly in immunized mice, indicating perturbed homeostasis. Moreover, WAS(-/-) nTreg cells failed to proliferate and to produce transforming growth factor beta upon T cell receptor (TCR)/CD28 triggering. WASP-dependent F-actin polarization to the site of TCR triggering might not be involved in WAS(-/-) nTreg cell defects because this process was also inefficient in wild-type (WT) nTreg cells. Compared with WT nTreg cells, WAS(-/-) nTreg cells showed reduced in vitro suppressor activity on both WT and WAS(-/-) effector T cells. Similarly, peripheral nTreg cells were present at normal levels in WAS patients but failed to suppress proliferation of autologous and allogeneic CD4(+) effector T cells in vitro. Thus, WASP appears to play an important role in the activation and suppressor function of nTreg cells, and a dysfunction or incorrect localization of nTreg cells may contribute to the development of autoimmunity in WAS patients.

Show MeSH
Related in: MedlinePlus