Activation of Mammalian Target of Rapamycin Controls the Loss of TCRζ in Lupus T Cells through HRES-1/Rab4-Regulated Lysosomal Degradation

Abstract

Persistent mitochondrial hyperpolarization (MHP) and enhanced calcium fluxing underlie aberrant T cell activation and death pathway selection in systemic lupus erythematosus. Treatment with rapamycin, which effectively controls disease activity, normalizes CD3/CD28-induced calcium fluxing but fails to influence MHP, suggesting that altered calcium fluxing is downstream or independent of mitochondrial dysfunction. In this article, we show that activity of the mammalian target of rapamycin (mTOR), which is a sensor of the mitochondrial transmembrane potential, is increased in lupus T cells. S ystemic lupus erythematosus (SLE)3 is an autoimmune disease of unknown etiology characterized by T and B cell dysfunction and production of antinuclear Abs (1). Dysregulation of cell death is thought to play a key role in driving antinuclear Ab production, since the source of immunogenic nuclear material is necrotic or apoptotic cells in SLE (2). There is enhanced spontaneous apoptosis of circulating T cells in SLE, which has been linked to chronic lymphopenia (3) and compartmentalized release of autoantigens (4). Paradoxically, there is decreased activation-induced T cell death in SLE (5-7), which may contribute to persistence of autoreactive cells.The mitochondria play crucial roles in activation and death pathway selection in T lymphocytes (2). Lupus T cells exhibit mitochondrial dysfunction, which is characterized by the elevation of the mitochondrial transmembrane potential (⌬ m ) or persistent mitochondrial hyperpolarization (MHP) and consequential ATP depletion, resulting in decrease of activation-induced apoptosis and predisposition of T cells for necrosis (6). ATP depletion in lupus T cells was recently confirmed by Krishnan et al. (8). We proposed that increased release of necrotic materials from T cells could drive disease pathogenesis by activating macrophages and dendritic cells and enhancing their capacity to produce NO and IFN-␣ in SLE (2). Indeed, dendritic cells exposed to necrotic, but not apoptotic, cells induce lupus like-disease in MRL mice and accelerate the disease of MRL/lpr mice (9).Enhanced T cell activation-induced calcium fluxing has been identified as a central defect in abnormal activation and cytokine production by lupus T cells (10). Induction of MHP and mitochondrial biogenesis by NO augments cytoplasmic calcium levels and regenerates the enhanced rapid calcium signaling profile of lupus T cells (11). Dysregulation of signaling through the TCR has also been shown to be a critical determinant of abnormal calcium fluxing in SLE (12, 13). The TCR/CD3 -chain (TCR) expression is diminished in SLE T cells, and it is functionally replaced by the FcR type I ␥-chain (FcRI␥), a protein normally found in other cell types (14). TCR signaling through FcRI␥ and its adaptor protein Syk is associated with elevated calcium fluxing but only in the absence of TCR (12). It has been shown that forced expression of The costs of publication of this article were defrayed in part by the payment of page charges. This ...

Metformin Suppresses Systemic Autoimmunity in Roquinsan/san Mice through Inhibiting B Cell Differentiation into Plasma Cells via Regulation of AMPK/mTOR/STAT3

“…It was reported that mTOR kinase activities of T cells are increased in SLE patients compared with matched healthy controls (6). Such enhanced mTOR activities could be reversed by rapamycin treatment (6).…”

“…Such enhanced mTOR activities could be reversed by rapamycin treatment (6). Suppression of mTOR activity with rapamycin treatment can markedly prolong survival, decrease anti-dsDNA Ab production, and ameliorate nephritis activity in MRL/lpr lupus-prone mice (7).…”

A 50‐Year‐Old Woman With Cowden Syndrome and Joint Pains

“…Another pathway for activation of mTOR in lupus T cells is from depletion of glutathione, which regulates the elevation of mitochondrial transmembrane potential or mitochondrial hyperpolarization (23). N-acetyl cysteine (NAC), which is an antioxidant and a precursor of GSH, inhibits mTOR and significantly improves disease activity and reduces anti-dsDNA in lupus patients (24).…”

T cell metabolism in autoimmune diseases

“…An increase in Akt activation has been demonstrated in the peripheral blood from SLE patients, concurrently with an up-regulation of the phosphorylation of one of its downstream targets, GSK3 [95], known as a negative regulator of cell cycle progression [96]. An abnormal activation of mTOR has been demonstrated in human SLE [97], and promising results in the treatment of the disease have been obtained with rapamycin, which could act by facilitating the differentiation of Treg cells and promoting the expansion of other subsets able to limit the T cell stimulation of auto-reactive B cells [98]. Beyond Akt and mTOR, a dysregulation in leptin expression has also been found in SLE patients [99; 100], but further studies are required to unlock the mechanisms that control its secretion.…”