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Rapamycin results in Bim-mediated loss of thymic regulatory T cells during development in organ culture.
Overall, Sarah A; van Driel, Ian R; Gleeson, Paul A.
Afiliación
  • Overall SA; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.
  • van Driel IR; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.
  • Gleeson PA; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia pgleeson@unimelb.edu.au.
Int Immunol ; 28(10): 513-518, 2016 10.
Article en En | MEDLINE | ID: mdl-27371614
Thymus-derived regulatory T cells (Tregs) are essential for the maintenance of immunological tolerance. Diverse signalling pathways contribute to thymic Treg cells (tTregs) development; however, the role of mammalian target of rapamycin (mTOR) remains unclear. Rapamycin is a well-characterized inhibitor of mTOR complex 1 signalling and a potent inducer of Treg cells in the periphery. However, the effect of rapamycin on the development of tTregs is poorly defined. Here we have used thymic organ culture to investigate the effect of rapamycin on tTreg development. We show that, contrary to its effect in the periphery, rapamycin inhibits the development of tTregs in wild-type thymi. The inhibition of tTregs by rapamycin could be rescued by a deficiency of Bim. However, rapamycin did not inhibit the development of antigen-specific TCR transgenic tTregs in response to exogenous peptide antigen, indicating that the development of thymic Foxp3+CD4+ cells was not intrinsically inhibited by rapamycin. Collectively our data demonstrate that rapamycin results in a reduction of tTregs because of Bim-mediated apoptosis of immature tTregs via a cell extrinsic mechanism. These findings are important not only for understanding the mechanism of tTreg induction but also for an appreciation of the impact of the clinical application of rapamycin.
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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Timo / Linfocitos T Reguladores / Sirolimus / Proteína 11 Similar a Bcl2 Límite: Animals Idioma: En Revista: Int Immunol Asunto de la revista: ALERGIA E IMUNOLOGIA Año: 2016 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Reino Unido
Buscar en Google
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PubMed Links

Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Timo / Linfocitos T Reguladores / Sirolimus / Proteína 11 Similar a Bcl2 Límite: Animals Idioma: En Revista: Int Immunol Asunto de la revista: ALERGIA E IMUNOLOGIA Año: 2016 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Reino Unido