Soluble GARP has potent antiinflammatory and immunomodulatory impact on human CD4⺠T cells.
Blood
; 122(7): 1182-91, 2013 Aug 15.
Article
em En
| MEDLINE
| ID: mdl-23818544
ABSTRACT
Glycoprotein A repetitions predominant (GARP) is expressed on the surface of activated human regulatory T cells (Treg) and regulates the bioavailability of transforming growth factor-ß (TGF-ß). GARP has been assumed to require membrane anchoring. To investigate the function of GARP in more detail, we generated a soluble GARP protein (sGARP) and analyzed its impact on differentiation and activation of human CD4⺠T cells. We demonstrate that sGARP efficiently represses proliferation and differentiation of naïve CD4⺠T cells into T effector cells. Exposure to sGARP induces Foxp3, decreases proliferation and represses interleukin (IL)-2 and interferon-γ production, resulting in differentiation of naïve T cells into induced Treg. This is associated with Smad2/3 phosphorylation and partially inhibited by blockade of TGF-ß signaling. Furthermore, in the presence of the proinflammatory cytokines IL-6 and IL-23, sGARP facilitates the differentiation of naïve T cells into Th17 cells. More important, in a preclinical humanized mouse model of xenogeneic graft-versus-host disease (GVHD), sGARP prevents T cell-mediated destructive inflammation by enhancing Treg and inhibiting T effector cell activity. These results demonstrate a crucial role of sGARP in modulation of peripheral tolerance and T effector cell function, opening the possibility to use sGARP as a potent immunomodulator of inflammatory diseases including transplant rejection, autoimmunity, and allergy.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Linfócitos T CD4-Positivos
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Doença Enxerto-Hospedeiro
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Inflamação
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Proteínas de Membrana
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Anti-Inflamatórios
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Blood
Ano de publicação:
2013
Tipo de documento:
Article