PMID- 24683191
OWN - NLM
STAT- MEDLINE
DCOM- 20140606
LR  - 20211203
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 192
IP  - 9
DP  - 2014 May 1
TI  - 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.
PG  - 4134-44
LID - 10.4049/jimmunol.1301859 [doi]
AB  - 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.
FAU - Kato, Hiroshi
AU  - Kato H
AD  - Division of Rheumatology, Department of Medicine, State University of New York, 
      Upstate Medical University, College of Medicine, Syracuse, NY 13210;
FAU - Perl, Andras
AU  - Perl A
LA  - eng
GR  - R01 AI072648/AI/NIAID NIH HHS/United States
GR  - AI072648/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140328
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Multiprotein Complexes)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adult
MH  - Cell Lineage/immunology
MH  - Cell Separation
MH  - Female
MH  - Flow Cytometry
MH  - Humans
MH  - Immunoblotting
MH  - Lupus Vasculitis, Central Nervous System/*immunology/metabolism
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Middle Aged
MH  - Multiprotein Complexes/*immunology/metabolism
MH  - T-Lymphocyte Subsets/*immunology/metabolism
MH  - T-Lymphocytes, Regulatory/*immunology/metabolism
MH  - TOR Serine-Threonine Kinases/*immunology/metabolism
MH  - Th17 Cells/*immunology/metabolism
PMC - PMC3995867
MID - NIHMS572033
COIS- Disclosure The authors have no financial conflicts of interest.
EDAT- 2014/04/01 06:00
MHDA- 2014/06/07 06:00
PMCR- 2015/05/01
CRDT- 2014/04/01 06:00
PHST- 2014/04/01 06:00 [entrez]
PHST- 2014/04/01 06:00 [pubmed]
PHST- 2014/06/07 06:00 [medline]
PHST- 2015/05/01 00:00 [pmc-release]
AID - jimmunol.1301859 [pii]
AID - 10.4049/jimmunol.1301859 [doi]
PST - ppublish
SO  - J Immunol. 2014 May 1;192(9):4134-44. doi: 10.4049/jimmunol.1301859. Epub 2014 
      Mar 28.