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 …

H Kato, A Perl - The Journal of Immunology, 2014 - journals.aai.org
H Kato, A Perl
The Journal of Immunology, 2014journals.aai.org
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 …
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.
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