mTORC1 couples immune signals and metabolic programming to establish Treg-cell function

Abstract

The mechanistic target of rapamycin (mTOR) pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct T cell fate decisions1. Activation of mTOR, comprised of mTORC1 and mTORC2 complexes, delivers an obligatory signal for proper activation and differentiation of effector CD4+ T cells2,3, whereas in the regulatory T cell (Treg) compartment, the Akt-mTOR axis is widely acknowledged as a crucial negative regulator of Treg de novo differentiation4–8 and population expansion9. However, whether mTOR signaling affects the homeostasis and function of Tregs remains largely unexplored. Here we show that mTORC1 signaling is a pivotal positive determinant of Treg function. Tregs have elevated steady-state mTORC1 activity compared to naïve T cells. Signals via T cell receptor (TCR) and IL-2 provide major inputs for mTORC1 activation, which in turn programs suppressive function of Tregs. Disruption of mTORC1 through Treg-specific deletion of the essential component Raptor leads to a profound loss of Treg suppressive activity in vivo and development of a fatal early-onset inflammatory disorder. Mechanistically, Raptor/mTORC1 signaling in Tregs promotes cholesterol/lipid metabolism, with the mevalonate pathway particularly important for coordinating Treg proliferation and upregulation of suppressive molecules CTLA-4 and ICOS to establish Treg functional competency. In contrast, mTORC1 does not directly impact the expression of Foxp3 or anti- and pro-inflammatory cytokines in Tregs, suggesting a non-conventional mechanism for Treg functional regulation. Lastly, we provide evidence that mTORC1 maintains Treg function partly through inhibiting the mTORC2 pathway. Our results demonstrate that mTORC1 acts as a fundamental ‘rheostat’ in Tregs to link immunological signals from TCR and IL-2 to lipogenic pathways and functional fitness, and highlight a central role of metabolic programming of Treg suppressive activity in immune homeostasis and tolerance.

Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune‐deficient mice

“…As mTOR inhibitors have entered clinical practice as anticancer drugs and are under evaluation as vaccine adjuvants, adjuncts to treating autoimmune disorders and to extend lifespan and healthspan, understanding the range of mTOR effects on immunity is crucial. Recent evidence shows that rapamycin specifically, and mTOR inhibit‐ion generally, improves important immune functions (Weichhart & Saemann, 2009; Ferrer et al ., 2010; Chi, 2012; Diken et al ., 2013; Keating et al ., 2013; Zeng et al ., 2013). We show that eRapa profoundly affected gene expression in seven important immune populations and suggest how these immune contributions could contribute to anticancer, lifespan extension, or healthspan extension, among other considerations.…”

“…Promoting autophagy, a known rapamycin effect, can augment immune memory, yet we found increased naïve T and B lymphocytes with long‐term eRapa. Given the extensive influences of mTOR on metabolism and the growing appreciation for links to immune outcomes (Xu et al ., 2012; Zeng et al ., 2013), mTOR metabolic effects in clinical and immune outcomes likely will now receive much deserved attention.…”

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

“…However, although the selective blockade of either mTORC1 or mTORC2 has been described to promote or hinder distinct T helper cell subsets 84 , the deletion of mTOR blocks T H 1, T H 2 and T H 17 cell polarization, indicating that both mTOR complexes have essential roles in the generation of inflammatory T helper cell subsets 83,[85][86][87] . By contrast, mTOR deficiency favours the induction of FOXP3 expression in vitro, and mTORC2 seems to be largely dispensable for T Reg cell stability and function in vivo 84,85,88 . In addition, although a requirement for some mTORC1 activity in tT Reg cells has been demonstrated 88 , rapamycin treatment (which preferentially inhibits mTORC1) actually promotes T Reg cell stability 59,89 , and hyperactivation of mTORC1 in T Reg cells drives IL-17 production and loss of FOXP3 expression 90 .…”

“…By contrast, mTOR deficiency favours the induction of FOXP3 expression in vitro, and mTORC2 seems to be largely dispensable for T Reg cell stability and function in vivo 84,85,88 . In addition, although a requirement for some mTORC1 activity in tT Reg cells has been demonstrated 88 , rapamycin treatment (which preferentially inhibits mTORC1) actually promotes T Reg cell stability 59,89 , and hyperactivation of mTORC1 in T Reg cells drives IL-17 production and loss of FOXP3 expression 90 . Furthermore, it seems that T Reg cell instability associated with increased mTOR activity is driven most prominently by activated mTORC2, which, by acting upstream of mTORC1, has the potential to activate parallel pathways to further destabilize T Reg cells 80,85 .…”

“…Complicating the role of each mTOR complex is the finding that loss of mTORC1 may destabilize T Reg cells by enhancing mTORC2 activation, as mTORC1 activity can negatively feedback on mTORC2 (REF. 88). Indeed, deciphering how numerous extracellular inputs are integrated within the cell to drive the plasticity of cells towards distinct functions is daunting, but mathematical modelling has successfully recapitulated the experimental observations described here and may provide an important platform to clarify this complexity 91 .…”