Homeostasis and transitional activation of regulatory T cells require c-Myc

Abstract

Regulatory T cell (Treg) activation and expansion occur during neonatal life and inflammation to establish immunosuppression, yet the mechanisms governing these events are incompletely understood. We report that the transcriptional regulator c-Myc (Myc) controls immune homeostasis through regulation of Treg accumulation and functional activation. Myc activity is enriched in Tregs generated during neonatal life and responding to inflammation. Myc-deficient Tregs show defects in accumulation and ability to transition to an activated state. Consequently, loss of Myc in Tregs results in an early-onset autoimmune disorder accompanied by uncontrolled effector CD4+ and CD8+ T cell responses. Mechanistically, Myc regulates mitochondrial oxidative metabolism but is dispensable for fatty acid oxidation (FAO). Indeed, Treg-specific deletion of Cox10, which promotes oxidative phosphorylation, but not Cpt1a, the rate-limiting enzyme for FAO, results in impaired Treg function and maturation. Thus, Myc coordinates Treg accumulation, transitional activation, and metabolic programming to orchestrate immune homeostasis.

mTOR signaling at the crossroads of environmental signals and T‐cell fate decisions

“…Additional studies using RAPTOR‐, mTOR‐, RagA‐ and RagB‐, RHEB‐ and RHEB2‐, or LAMTOR1 (a component of the Ragulator complex)‐deficient Treg cells show that effector Treg (eTreg) cells, including T‐follicular regulatory (Tfr) cells, require mTOR signaling for their generation or homeostasis 23,61,115,207,208,209 . Similar observation is found in Treg cells deficient in c‐MYC, the transcription factor that frequenlty interplays with mTORC1 in programming anabolic metabolism 210 115 demonstrating that mTOR signaling has discrete functions during pTreg‐cell formation and maintenance.…”

“…23,61,115,207,208,209 Similar observation is found in Treg cells deficient in c-MYC, the transcription factor that frequenlty interplays with mTORC1 in programming anabolic metabolism. 210 Furthermore, mTOR signaling supports the accumulation of pTreg cells in vivo, 115 demonstrating that mTOR signaling has discrete functions during pTreg-cell formation and maintenance.…”

Signaling networks in immunometabolism

“…218 Further, mice with Treg cell-specific CPT1a deficiency show normal immune homeostasis, suggesting that CPT1a-dependent FAO is dispensable for Treg cell function for establishment of immune tolerance in vivo. 218,219 These discrepancies may be, in part, attributable to off-target effects of high-dose etomoxir, such as depletion of coenzyme A levels that are essential for driving induction of fatty acid synthesis among other functions. 220 Memory T cell responses are also important for anti-tumor immunity.…”

Tissue Nutrient Environments and Their Effect on Regulatory T Cell Biology

“…CPT1a loss, the predominant isoform in lymphocytes, inhibits oxidation of LCFA in Tregs. However, this does not affect the development of tissue resident Tregs, de novo polarization, or suppression, suggesting that Tregs most likely depend on SCFA and MCFA for FAO (23,36). Nevertheless, this does not mean that LCFAs do not modulate Treg metabolism.…”

“…The ETC comprises four subunits (Complex I-IV) and an ATP synthase (Figure 1). Treg-specific deletion of ETC components remarkably impair Treg suppressive function, underpinning a fundamental function for mitochondrial OXPHOS in Tregs (23)(24)(25). The TCA cycle is driven by the oxidation of Acetyl CoA, which could be generated from glucose-derived pyruvate through the pyruvate dehydrogenase (PDH) complex (Figure 1).…”