Mechanistic Target of Rapamycin Activation Triggers IL-4 Production and Necrotic Death of Double-Negative T Cells in Patients with Systemic Lupus Erythematosus

Abstract

The mechanistic target of rapamycin (mTOR) is recognized as a sensor of mitochondrial dysfunction and effector of T-cell lineage development, however, its role in autoimmunity, including systemic lupus erythematosus, remains unclear. Here, we prospectively evaluated mitochondrial dysfunction and mTOR activation in PBL relative to SLE disease activity index (SLEDAI) during 274 visits of 59 patients and 54 matched healthy subjects. Partial least square-discriminant analysis identified 15 of 212 parameters that accounted for 70.2% of the total variance and discriminated lupus and control samples (p<0.0005); increased mitochondrial mass of CD3+/CD4−/CD8− double-negative (DN) T cells (p=1.1×10−22) and FoxP3 depletion in CD4+/CD25+ T cells were top contributors (p=6.7×10−7). Prominent necrosis and mTOR activation were noted in DN T cells during 15 visits characterized by flares (SLEDAI increase ≥4) relative to 61 visits of remission (SLEDAI decrease ≥4). mTOR activation in DN T cells was also noted at pre-flare visits of SLE patients relative to those of stable disease or healthy controls. DN lupus T cells showed increased production of IL-4, which correlated with depletion of CD25+/CD19+B cells. Rapamycin treatment in vivo blocked the IL-4 production and necrosis of DN T cells, increased the expression of FoxP3 in CD25+/CD4+T cells, and expanded CD25+/CD19+ B cells. These results identify mTOR activation to be a trigger of IL-4 production and necrotic death of DN T cells in patients with SLE.

Akt-Dependent Enhanced Migratory Capacity of Th17 Cells from Children with Lupus Nephritis

“…These results are in line with earlier studies demonstrating enhanced mTOR activation in lupus T cells (13,14).…”

“…Moreover, the inhibition of mTOR by rapamycin reduces disease activity in patients with SLE (12). Previous studies also demonstrated that double-negative T cells from rapamycin-treated SLE patients display reduced necrosis and IL-4 production (14). Additionally, the PI3K/Akt/mTORC1 pathway controls the differentiation of Th17 cells by regulating the nuclear translocation of RORg and other factors (37).…”

“…mTOR activity is increased in lupus T cells (13). Moreover, treatment with rapamycin improves disease activity in SLE patients (12) and reduces necrosis and IL-4 production of double-negative lupus T cells (14). Additionally, mTOR signaling is required for Th17 cell differentiation (11) and IL-17 is critically involved in the pathogenesis of LN (6, 7).…”

“…Treatment of SLE patients with rapamycin reduces disease activity (12), indicating the clinical significance. Moreover, mTOR activity is increased in lupus T cells and is involved in the enhanced production of IL-17 and especially of IL-4 in SLE patients (13,14). mTORC1 is activated downstream of PI3K/Akt signaling, and inhibition of PI3K or Akt signaling prevents Th17 cytokine induction in memory T cells (15).…”

m-TOR Inhibitors in the Current Practice

“…This regulatory T cells together with CD4+CD25-cells increased STAT3 and STAT5 phosphorylation and enhance the differentiation of CD8+ T cells into memory cells in mice inoculated with lymphocytic choriomeningitis virus. Prospective clinical trial in SLE patients with sirolimus is ongoing [74][75][76]. Scleroderma m-TOR can plays a role in fibrotic diseases and autoimmunity, and blockade of the mTORC pathway through blocking the profibrotic effects of TGF-β can play a part in the treatment of scleroderma (or systemic sclerosis), however, this approach is currently under investigation [77].…”