title: 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. 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.
authors.affiliation: Division of Rheumatology, Department of Medicine, College of Medicine, Upstate Medical University, State University of New York, Syracuse, NY 13210, USA.
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Lai
authors.forename: Rebecca
authors.initials: R
authors.lastname: Borsuk
authors.forename: Ashwini
authors.initials: A
authors.lastname: Shadakshari
authors.forename: Jianghong
authors.initials: J
authors.lastname: Yu
authors.forename: Maha
authors.initials: M
authors.lastname: Dawood
authors.forename: Ricardo
authors.initials: R
authors.lastname: Garcia
authors.forename: Lisa
authors.initials: L
authors.lastname: Francis
authors.forename: Hajra
authors.initials: H
authors.lastname: Tily
authors.forename: Adam
authors.initials: A
authors.lastname: Bartos
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Faraone
authors.forename: Paul
authors.initials: P
authors.lastname: Phillips
authors.forename: Andras
authors.initials: A
authors.lastname: Perl
mesh_terms: D000328:Adult; D000368:Aged; D002986:Clinical Trials as Topic; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D015847:Interleukin-4 / Q000096:biosynthesis / Q000592:standards*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D020123:Sirolimus / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000276:immunology* / Q000378:metabolism; D055815:Young Adult
chemical_list: C508598:IL4 protein, human; D007166:Immunosuppressive Agents; D015847:Interleukin-4; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
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