title: Mechanistic target of rapamycin complex 1 expands Th17 and IL-4+ CD4-CD8- double-negative T cells and contracts regulatory T cells in systemic lupus erythematosus.
abstract: The mechanistic target of rapamycin (mTOR) is activated in CD4(-)CD8(-) double-negative (DN) T cells and its blockade is therapeutic in systemic lupus erythematosus (SLE) patients. Murine studies showed the involvement of mTOR complex 1 (mTORC1) and 2 (mTORC2) in the differentiation of Th1/Th17 cells and Th2 cells, respectively. In this study, we investigated the roles of mTORC1 and mTORC2 in T cell lineage development in SLE and matched healthy control (HC) subjects. mTORC1 activity was increased, whereas mTORC2 was reduced, as assessed by phosphorylation of their substrates phosphorylated S6 kinase 1 or phosphorylated S6 ribosomal protein and phosphorylated Akt, respectively. Rapamycin inhibited mTORC1 and enhanced mTORC2. IL-4 expression was increased in freshly isolated CD8(+) lupus T cells (SLE: 8.09 ± 1.93%, HC: 3.61 ± 0.49%; p = 0.01). DN T cells had greater IL-4 expression than CD4(+) or CD8(+) T cells of SLE patients after 3-d in vitro stimulation, which was suppressed by rapamycin (control: 9.26 ± 1.48%, rapamycin: 5.03 ± 0.66%; p < 0.001). GATA-3 expression was increased in CD8(+) lupus T cells (p < 0.01) and was insensitive to rapamycin treatment. IFN-γ expression was reduced in all lupus T cell subsets (p = 1.0 × 10(-5)) and also resisted rapamycin. IL-17 expression was increased in CD4(+) lupus T cells (SLE: 3.62 ± 0.66%, HC: 2.29 ± 0.27%; p = 0.019), which was suppressed by rapamycin (control: 3.91 ± 0.79%, rapamycin: 2.22 ± 0.60%; p < 0.001). Frequency of regulatory T cells (Tregs) was reduced in SLE (SLE: 1.83 ± 0.25%, HC: 2.97 ± 0.27%; p = 0.0012). Rapamycin inhibited mTORC1 in Tregs and promoted their expansion. Neutralization of IL-17, but not IL-4, also expanded Tregs in SLE and HC subjects. These results indicate that mTORC1 expands IL-4(+) DN T and Th17 cells, and contracts Tregs in SLE.
authors.affiliation: Division of Rheumatology, Department of Medicine, State University of New York, Upstate Medical University, College of Medicine, Syracuse, NY 13210;
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kato
authors.forename: Andras
authors.initials: A
authors.lastname: Perl
mesh_terms: D000328:Adult; D019070:Cell Lineage / Q000276:immunology; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D020945:Lupus Vasculitis, Central Nervous System / Q000276:immunology* / Q000378:metabolism; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008875:Middle Aged; D046912:Multiprotein Complexes / Q000276:immunology* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000276:immunology* / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases