[64] This binds to AU-rich elements in the 3′ untranslated region of the interferon-γ mRNA and blocks its translation, but only if the substrate for GAPDH, glyceraldehyde 3-phosphate, is unavailable. If activated T cells are deprived of glucose, and instead provided with galactose, then glycolysis cannot take place, and yet the T cells still activate and proliferate (because galactose provides alternative precursors

for nucleotide synthesis via the pentose phosphate pathway), but now because GAPDH has no substrate, it blocks the translation of interferon-γ. Under these conditions the T cells also then express other markers of T-cell exhaustion such as programmed death 1.[64] The corollary of this is that inducing glycolysis, for example by mTOR activation, will tend to promote Navitoclax research buy effector cell differentiation.

There are also suggestions that there may be other examples where metabolic enzymes, for example hexokinase[65] and IDO,[26] can have a secondary, signalling role in dendritic cell differentiation. Inhibition of mTOR therefore seems to be associated with tolerance and FOXP3+ Treg cell induction, and this appeared to be confirmed by T-cell-specific Everolimus in vitro mTOR knockout mice, which develop an excess of FOXP3+ Treg cells over Th1 and Th2 effector cells.[18] Recent data, however, from FOXP3-Cre.Raptorfl/fl mice where TORC1 activity has been specifically ROS1 knocked out in FOXP3+ Treg cells, indicates that TORC1 activation is still required for Treg cells to function, as evidenced by the development of an autoinflammatory condition very similar to scurfy or FOXP3-deficient mice.[66] CD4-Cre.Raptorfl/fl mice, lacking TORC1 activity in all T cells, however, did not develop disease, presumably because this also compromised the effector T cells. This raises the possibility that the optimal induction and expansion of FOXP3+ Treg cells takes place in the nutrient-depleted microenvironments associated with tolerance, but the Treg cells

only become fully active and proliferative when there is inflammation that needs to be controlled, which requires a re-activation of their mTOR pathway. Interestingly, it had previously been postulated that the optimal functional induction of FOXP3+ Treg cells required alternate cycles or oscillations of mTOR inhibition, first to promote induction, and subsequently mTOR activation to promote proliferation.[67] CD8+ effector T cells also need to rapidly proliferate and expand, particularly in response to viral infection, and so would be expected to require mTOR activation, but perhaps surprisingly, it has been shown that mTOR inhibition with rapamcyin actually promotes a better protective response during vaccination.