Metabolic control of T cell activation and death in SLE

Abstract

Systemic lupus erythematosus (SLE) is characterized by abnormal T cell activation and death, processes which are crucially dependent on the controlled production of reactive oxygen intermediates (ROI) and of ATP in mitochondria. The mitochondrial transmembrane potential (Δψ_m) has conclusively emerged as a critical checkpoint of ATP synthesis and cell death. Lupus T cells exhibit persistent elevation of Δψ_m or mitochondrial hyperpolarization (MHP) as well as depletion of ATP and glutathione which decrease activation-induced apoptosis and instead predispose T cells for necrosis, thus stimulating inflammation in SLE. NO-induced mitochondrial biogenesis in normal T cells accelerates the rapid phase and reduces the plateau of Ca²⁺ influx upon CD3/CD28 co-stimulation, thus mimicking the Ca²⁺ signaling profile of lupus T cells. Treatment of SLE patients with rapamycin improves disease activity, normalizes CD3/CD28-induced Ca²⁺ fluxing but fails to affect MHP, suggesting that altered Ca²⁺ fluxing is downstream or independent of mitochondrial dysfunction. Understanding the molecular basis and consequences of MHP is essential for controlling T cell activation and death signaling in SLE.

Introduction

Abnormal T cell activation and cell death underlie the pathology of SLE [1]. Potentially autoreactive T and B lymphocytes are removed by apoptosis during development and after completion of an immune response. Paradoxically, lupus T cells exhibit both enhanced spontaneous apoptosis and defective activation-induced cell death [2]. Increased spontaneous apoptosis has been linked to chronic lymphopenia [2] and compartmentalized release of nuclear autoantigens in patients with SLE [3]. By contrast, defective activation-induced cell death (AICD) may be responsible for persistence of autoreactive cells [2] (Table 1).

Both cell proliferation and apoptosis are energy-dependent processes. Energy in the form of ATP is provided through glycolysis and oxidative phosphorylation. The mitochondrion, the site of oxidative phosphorylation, has long been identified as a source of energy and cell survival [2]. The synthesis of ATP is driven by an electrochemical gradient across the inner mitochondrial membrane maintained by an electron transport chain and the membrane potential (Δψ_m, negative inside and positive outside). A small fraction of electrons react directly with oxygen and form reactive oxygen intermediates (ROI). The Δψ_m is regulated by the supply of reducing equivalents (NADH/NAD + NADPH/NADP + GSH) and the production of ROI and nitric oxide (NO) [4]. Regeneration of GSH by glutathione reductase from its oxidized form, GSSG, and synthesis of NO depend on NADPH produced by the pentose phosphate pathway (PPP) [2]. While disruption of the mitochondrial membrane potential Δψ_m has been proposed as the point of no return in apoptosis, elevation of Δψ_m or mitochondrial hyperpolarization (MHP) occurs prior to activation of caspases, phosphatidylserine (PS) externalization and disruption of Δψ_m in Fas- [5], H₂O₂- [6], and NO-induced apoptosis [7]. MHP is also triggered by T cell receptor (TCR) stimulation that is associated with transient inhibition of F₀F₁-ATPase, ATP depletion, and sensitization to necrosis, suggesting that Δψ_m elevation is a critical checkpoint of T cell fate decisions [8]. Importantly, lupus T cells exhibit persistent MHP and ATP depletion which causes predisposition to death by necrosis that is highly pro-inflammatory [2]. The mammalian target of rapamycin (mTOR) is located in the outer mitochondrial membrane and serves as a sensor of the Δψ_m in T cells [9]. Focused on targeting MHP for treatment of lupus patients resistant or intolerant to conventional immunosuppressants, rapamycin improved disease activity and normalized baseline and T cell activation-induced Ca²⁺ fluxing without affecting MHP [10]. These findings suggested that mTOR represents a gate keeper between MHP and altered Ca²⁺ signaling in SLE. The present review will focus on establishing the hierarchy of the metabolic pathways that underlie and mediate the consequences MHP and identify checkpoints that can be targeted for therapeutic intervention in SLE (Fig. 1).