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Downregulation of TGF-ßRII in T effector cells leads to increased resistance to TGF-ß-mediated suppression of autoimmune responses in type I diabetes.
Kawamoto, Koichi; Pahuja, Anil; Nettles, Adam; Honkanen-Scott, Minna; Bansal-Pakala, Pratima.
Afiliação
  • Kawamoto K; Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
Autoimmunity ; 45(4): 310-9, 2012 Jun.
Article em En | MEDLINE | ID: mdl-22390157
ABSTRACT
Tregs play an important role in controlling immune responses, particularly autoimmunity. In NOD mouse model, an excellent model for autoimmune diabetes, transfer of Tregs was shown to prevent diabetes, whereas depletion of Tregs in vivo enhanced disease progression, suggesting that Treg dysfunction contributes to the pathogenesis of diabetes. However, the mechanisms leading to Treg dysfunction and their role in diabetes progression has remained unclear. In this study we assessed quantitative and qualitative changes in Tregs during the development of autoimmune diabetes in NOD. We compared female NOD with males that have similar predisposition to but a lower incidence of diabetes and found that Treg numbers remained unchanged between 6 to 16 weeks of age in both groups. Although female Tregs produced lower TGF-ß compared to male, regulatory function of female Tregs was only marginally inferior to male upon GAD65 autoantigen stimulation. GAD65-reactive female Teffectors were more responsive and progressively became refractory to regulation compared to male effectors, in part due to lower expression of TGF-ß RII, accounting for reduced sensitivity to Tregs. Moreover, we unexpectedly found that TGF-ß suppressed IFN-γ production to GAD65 antigen in male, not in female responders. These data suggest that TGF-ß plays a major role in Teff resistance to regulation and Treg dysfunction, and may account for autoimmune diabetes. Our study implies that development of a successful supplemental Treg therapy for halting autoimmunity may require further understanding of Teff responses to regulation in order to generate highly effective Tregs.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Autoimunidade / Fator de Crescimento Transformador beta / Linfócitos T Reguladores / Receptores de Fatores de Crescimento Transformadores beta / Diabetes Mellitus Tipo 1 Tipo de estudo: Prognostic_studies / Qualitative_research Limite: Animals Idioma: En Revista: Autoimmunity Assunto da revista: ALERGIA E IMUNOLOGIA Ano de publicação: 2012 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Autoimunidade / Fator de Crescimento Transformador beta / Linfócitos T Reguladores / Receptores de Fatores de Crescimento Transformadores beta / Diabetes Mellitus Tipo 1 Tipo de estudo: Prognostic_studies / Qualitative_research Limite: Animals Idioma: En Revista: Autoimmunity Assunto da revista: ALERGIA E IMUNOLOGIA Ano de publicação: 2012 Tipo de documento: Article País de afiliação: Estados Unidos