Intracellular sensors of immunity and allogeneic hematopoietic stem cell transplantation - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 433

mTOR in the immune system has long been recognized through the finding
that the immunosuppressive macrolide rapamycin acts to inhibit mTOR
[123,124] . A number of studies have reported the use of gene targeting to
disrupt mTOR function in lymphocytes [124,125] . Alongside analyses of the
effects of rapamycin in vivo, these studies have confirmed an essential role
for mTOR signaling in T-cell differentiation and DC development and func-
tion [126] . Here we focus only on the metabolic role of mTOR and not on the
direct immune effects. The mTOR kinase integrates cues from nutrients and
growth factors, acting as a nexus point for cellular signals to control growth,
metabolism, and longevity [15] .

mTOR is the catalytic subunit of two multiprotein complexes, mTOR com-
plexes 1 and 2 (mTORC1/mTORC2), which are associated with the adaptor
proteins Raptor and Rictor, respectively [124-126] . Deregulation of either of
mTOR's two complexes, mTORC1 or mTORC2, leads to diseases of metabo-
lism, including cancer and diabetes [15] . Rapamycin binds the intracellular
protein FK506-binding protein of 12 kDa (FKBP12) and the rapamycin-FKBP12
complex specifically inhibits mTORC1 [15] . Interestingly, studies using novel
active-site mTOR inhibitors suggest that rapamycin-mediated inhibition
of mTORC1 is incomplete [124-126] . By contrast, mTORC2 is insensitive to
rapamycin, although there is some evidence indicating that prolonged rapa-
mycin treatment may partially inhibit mTORC2 formation [126] .

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mTOR functions as a critical regulator and sensor of the metabolic status
of cells. Its activity is also regulated by the availability of amino acids, in
particular leucine [127,128] . Amino acids enable activation of Rag family
GTPases that associate with Raptor and facilitate mTORC1 activation [124-
126] . By contrast, when cells are deprived of nutrients, mTOR activation is
suppressed [124-126] . This is in part facilitated by activation of AMP-acti-
vated protein kinase (AMPK). AMPK is activated as a result of reduced levels
of cellular ATP and results in inhibition of mTORC1 activity [127,128] . Only
a few substrates for mTORC1 and mTORC2 have been described. The best
characterized substrates for mTORC1 are ribosomal protein S6 kinase and
elongation factor 4E-binding protein 1, which regulates mRNA translation
[124-126,127,128] .

mTORC1 is also an important regulator of autophagy, which is a conserved
pathway by which cells dispose of intracellular organelles and protein aggre-
gates [129] . Autophagy is negatively regulated by mTORC1 and is initiated
when mTORC1 is inhibited by either treatment of cells with rapamycin or
conditions of nutrient starvation [15,129] . mTORC1 can be reactivated upon
prolonged cell starvation in an autophagy-dependent manner [15,129] .
Autophagy pathways are critical for many important immunological pro-
cesses such as degradation of intracellular pathogens and antigen presen-
tation [130] . A number of recent studies have highlighted the importance
of autophagy in DC function and have shown that manipulation of these
processes represents an important immune evasion tactic for several intra-
cellular pathogens [130] . Conditional deletion of Atg5, a critical autoph-
agy gene, reduced the ability of DCs to prime viral-specific CD4 + T-cell
responses in vivo. This was not a result of altered DC migration or defects
in endocytosis or phagocytosis, because Atg5 (autophagy) is important for
delivery of lysosomal proteases to phagosomes and subsequent antigen