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Murine dendritic cell rapamycin-resistant and rictor-independent mTOR controls IL-10, B7-H1, and regulatory T-cell

Brian R Rosborough1, Dàlia Raïch-Regué, Benjamin M Matta

  • 1Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Blood
|February 28, 2013
PubMed

Insights

Rapamycin-sensitive mTORC1 promotes effector T cells, while a rapamycin-insensitive mTOR pathway restrains regulatory T cell induction. This reveals a novel mTOR mechanism impacting immune responses.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • Mammalian target of rapamycin (mTOR) is a critical kinase regulating immune cell function.
  • mTOR operates in two complexes, mTORC1 and mTORC2, with distinct roles.
  • Rapamycin (RAPA) selectively inhibits mTORC1, paradoxically reducing IL-10 and B7-H1 in dendritic cells (DCs).

Purpose of the Study:

  • To elucidate the mechanism behind RAPA's paradoxical effects on IL-10 and B7-H1 expression in DCs.
  • To investigate the role of RAPA-insensitive mTOR pathways in DC-mediated immune regulation.
  • To define the distinct roles of RAPA-sensitive and RAPA-insensitive mTOR signaling in T cell differentiation.

Main Methods:

  • Utilized catalytic mTOR inhibitors.
  • Employed dendritic cells genetically modified to lack mTORC2.
  • Analyzed signal transducer and activator of transcription 3 (STAT3)-mediated gene expression.
  • Assessed the induction of regulatory T cells (Tregs) by DCs.

Main Results:

  • Identified a RAPA-insensitive and mTORC2-independent mTOR mechanism controlling IL-10 and B7-H1 expression during DC maturation.
  • Demonstrated that catalytic mTOR inhibition promotes B7-H1-dependent and IL-1β-dependent Treg induction by DCs.
  • Established that RAPA-sensitive mTORC1 promotes effector T cell expansion, while RAPA-insensitive mTORC1 restrains Treg induction.

Conclusions:

  • Defined a novel immunoregulatory pathway involving distinct mTORC1 activities.
  • Characterized the first known RAPA-insensitive mTOR pathway not solely mediated by mTORC2.
  • Highlighted implications for using catalytic mTOR inhibitors in treating inflammatory diseases.

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