Metabolic control of regulatory T cell stability and function by TRAF3IP3 at the lysosome

Abstract

Metabolic programs are crucial for regulatory T (T reg) cell stability and function, but the underlying mechanisms that regulate T reg cell metabolism are elusive. Here, we report that lysosomal TRAF3IP3 acts as a pivotal regulator in the maintenance of T reg cell metabolic fitness. T reg-specific deletion of impairs T reg cell function, causing the development of inflammatory disorders and stronger antitumor T cell responses in mice. Excessive mechanistic target of rapamycin complex 1 (mTORC1)-mediated hyper-glycolytic metabolism is responsible for the instability of TRAF3IP3-deficient T reg cells. Mechanistically, TRAF3IP3 restricts mTORC1 signaling by recruiting the serine-threonine phosphatase catalytic subunit (PP2Ac) to the lysosome, thereby facilitating the interaction of PP2Ac with the mTORC1 component Raptor. Our results define TRAF3IP3 as a metabolic regulator in T reg cell stability and function and suggest a lysosome-specific mTORC1 signaling mechanism that regulates T reg cell metabolism.

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

“…By binding TRAF3IP3, the phosphatase PP2A interacts with RAPTOR on the lysosome and subsequently inactivates mTORC1 activity. Treg cell‐specific deficiency of PP2A 212 or TRAF3IP3 213 dampens the suppressive function of Treg cells and reduces the stability of Treg cells, which is ultimately associated with the development of autoimmunity. Ablation of both PP2A and TRAF3IP3 induces aberrant mTOR activation, and treatment with rapamycin ameliorates the autoimmune disease in mice with Treg‐specific deletion of PP2A or restores the lineage stability of TRAF3IP3‐deficient Treg cells.…”

TRAF3IP3 negatively regulates cytosolic RNA induced anti-viral signaling by promoting TBK1 K48 ubiquitination

“…Traf3ip3 deficiency potentiates the type I interferon response. TRAF3IP3 was shown to be essential for T and B cell development [32][33][34] . To specifically investigate the role of TRAF3IP3 in innate immunity, we generated Traf3ip3 fl/fl Lyz2-Cre + mice, which harbored deletion of the loxP-flanked Traf3ip3 (Traf3ip3 fl/fl ) specifically in myeloid cells via Cre recombinase under control of the myeloidcell specific promoter Lyz2 (Lyz2-Cre).…”

“…6a, b). TRAF3IP3 was found to inhibit MTOR signaling in Treg cells 32 . The data with 4E-BP1 was varied in that we observed no difference in the phosphorylation of 4E-BP1 IB: α-TBK1 after poly(I:C) transfection and a modest increase its phosphorylation in Traf3ip3 fl/fl Lyz2-Cre + BMDMs than in Traf3ip3 fl/fl Lyz2-Cre − BMDMs (Fig.…”

“…Later studies showed that TRAF3IP3 is required for the maturation of double positive T cell to mature T cell by facilitating ERK signaling 33 . In addition, a more recent study showed that TRAF3IP3 is essential for maintaining regulatory T cell stability and function by suppressing the mechanistic target of rapamycin complex 1 (mTORC1) 32 . Cytosolic RNA stimulation is known to activate ERK signaling but inhibit mTORC1 signaling 43,44 , which is also consistent with data shown in wildtype controls.…”

“…TRAF3-interacting protein 3 (TRAF3IP3, also known as TRAF3-interacting JNK-activating modulator (T3JAM)) was initially identified as a TRAF3 interacting protein 31 , although significant time lapsed before its physiological function was studied with gene deletion mice. Studies show TRAF3IP3 is required for B and T cell development, as well as for the maintenance of regulatory T cell functional stability [32][33][34] . By contrast, here we find that TRAF3IP3 is well expressed by cells within the myeloid lineage, where its function in innate immunity is unclear.…”