TORC1 and TORC2 selectively regulate CD4+ T helper cell lineage differentiation (50.35)
| Autor: | Greg Delgoffe, Adam Waickman, Kristen Pollizzi, Bo Xiao, Paul Worley, Jonathan Powell |
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| Rok vydání: | 2010 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 184:50.35-50.35 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | The mammalian target of rapamycin (mTOR) is a highly conserved serine-threonine kinase that regulates cell division, survival, and translation. Downstream mTOR signals via two functionally distinct complexes, TORC1 and TORC2. We have previously shown T cells deficient in mTOR fail to differentiate into Th1, Th2, or Th17 cells and instead become Foxp3+ regulatory cells. We further dissected mTOR signaling in T cell differentiation by deleting Rheb (the activator of TORC1) and rictor (an essential TORC2 subunit). T cells lacking Rheb selectively lack TORC1 activity, and, like mTOR mutants, fail to differentiate into Th1 or Th17 cells when skewed. However, Rheb-deficient T cells retain their ability to become Th2 cells. This is due in part to diminished STAT4 and STAT3 activation, but elevated STAT6 activation. Alternatively, rictor-deficient cells specifically lack TORC2 activity, and fail to become Th2 cells when skewed. However, they retain the ability to become Th1 and Th17 cells, with a pattern of STAT activation that inversely correlates with TORC1 mutants. Interestingly, neither TORC1 nor TORC2 deficiency alone is sufficient to induce Treg differentiation. In vivo, TORC1 deficiency protects against EAE while TORC2 deficiency leads to accelerated disease. Our data support a novel paradigm in which TCR engagement in the absence of mTOR defaults to a regulatory fate, and TORC1 and TORC2 activation selectively regulate T cell effector lineage differentiation. |
| Databáze: | OpenAIRE |
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