Murine Dendritic Cell Rapamycin-resistant and Rictor-independent MTOR Controls IL-10, B7-H1, and Regulatory T-cell Induction

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2013 Feb 28

PMID 23444404

Citations 32

Authors

Brian R Rosborough

Dalia Raich-Regue

Benjamin M Matta

Keunwook Lee

Boyi Gan

Ronald A DePinho

Holger Hackstein

Mark Boothby

Heth R Turnquist

Angus W Thomson

Affiliations

Soon will be listed here.

Abstract

Mammalian target of rapamycin (mTOR) is an important, yet poorly understood integrative kinase that regulates immune cell function. mTOR functions in 2 independent complexes: mTOR complex (mTORC) 1 and 2. The immunosuppressant rapamycin (RAPA) inhibits mTORC1 but not mTORC2 and causes a paradoxical reduction in anti-inflammatory interleukin (IL) 10 and B7-homolog 1 (B7-H1) expression by dendritic cells (DCs). Using catalytic mTOR inhibitors and DCs lacking mTORC2, we show that restraint of signal transducer and activator of transcription 3-mediated IL-10 and B7-H1 expression during DC maturation involves a RAPA-insensitive and mTORC2-independent mTOR mechanism. Relatedly, catalytic mTOR inhibition promotes B7-H1-dependent and IL-1β-dependent DC induction of regulatory T cells (Tregs). Thus, we define an immunoregulatory pathway in which RAPA-sensitive mTORC1 in DCs promotes effector T-cell expansion and RAPA-insensitive mTORC1 restrains T(reg) induction. These findings identify the first known RAPA-insensitive mTOR pathway that is not mediated solely by mTORC2 and have implications for the use of catalytic mTOR inhibitors in inflammatory disease settings.

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