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

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-gamma expression was reduced in all lupus T cell subsets (p = 1.0 x 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. The Journal of Immunology, 2014, 192: 4134-4144.