Mechanistic Target of Rapamycin Activation Triggers IL-4 Production and Necrotic Death of Double-Negative T Cells in Patients with Systemic Lupus Erythematosus
- 1 September 2013
- journal article
- Published by The American Association of Immunologists
- Vol. 191 (5), 2236-2246
- https://doi.org/10.4049/jimmunol.1301005
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. In this study, we prospectively evaluated mitochondrial dysfunction and mTOR activation in PBLs relative to the Systemic Lupus Erythematosus 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 preflare visits of SLE patients relative to those with 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.Keywords
This publication has 60 references indexed in Scilit:
- Necrostatin-1 analogues: critical issues on the specificity, activity and in vivo use in experimental disease modelsCell Death & Disease, 2012
- Web-based inference of biological patterns, functions and pathways from metabolomic data using MetaboAnalystNature Protocols, 2011
- Mammalian target of rapamycin activation underlies HSC defects in autoimmune disease and inflammation in miceJCI Insight, 2010
- The S1P1-mTOR axis directs the reciprocal differentiation of TH1 and Treg cellsNature Immunology, 2010
- PI3 kinase signalling blocks Foxp3 expression by sequestering Foxo factorsThe Journal of Experimental Medicine, 2010
- mTOR and GSK-3 shape the CD4+ T-cell stimulatory and differentiation capacity of myeloid DCs after exposure to LPSBlood, 2010
- The mTOR Kinase Differentially Regulates Effector and Regulatory T Cell Lineage CommitmentImmunity, 2009
- Metabolic control of T cell activation and death in SLEAutoimmunity Reviews, 2008
- Antagonistic nature of T helper 1/2 developmental programs in opposing peripheral induction of Foxp3 + regulatory T cellsProceedings of the National Academy of Sciences, 2007
- Derivation of the sledai. A disease activity index for lupus patientsArthritis & Rheumatism, 1992