PMID- 29161463
OWN - NLM
STAT- MEDLINE
DCOM- 20190111
LR  - 20211204
IS  - 2326-5205 (Electronic)
IS  - 2326-5191 (Print)
IS  - 2326-5191 (Linking)
VI  - 70
IP  - 3
DP  - 2018 Mar
TI  - Blockade of Treg Cell Differentiation and Function by the 
      Interleukin-21-Mechanistic Target of Rapamycin Axis Via Suppression of Autophagy 
      in Patients With Systemic Lupus Erythematosus.
PG  - 427-438
LID - 10.1002/art.40380 [doi]
AB  - OBJECTIVE: The mechanistic target of rapamycin (mTOR) has become a therapeutic 
      target in systemic lupus erythematosus (SLE). In T cells, mTOR plays a central 
      role in lineage specification, including development of regulatory cells (Treg 
      cells). This study sought to investigate whether mTOR is activated within Treg 
      cells and whether this contributes to the depletion and dysfunction of Treg cells 
      in patients with SLE. METHODS: Activities of mTOR complexes 1 (mTORC1) and 2 
      (mTORC2) were examined by quantifying phosphorylation of translation initiation 
      factor 4E-binding protein 1, S6 kinase, and Akt in SLE patients relative to age- 
      and sex-matched female healthy control subjects. Polarization of Treg cells from 
      naive CD4+ T cells was assessed in the presence of interleukin-6 (IL-6), IL-17, 
      and IL-21. The suppressor function of sorted CD4+CD25+ Treg cells was measured by 
      determining their impact on the proliferation of autologous CD4+CD25- responder T 
      cells. Treg cell expression of FoxP3, GATA-3, and CTLA-4 was monitored by flow 
      cytometry. Autophagy was assessed using immunoblotting of light chain 3 
      lipidation. The effect of mTOR blockade was evaluated by testing the impact of 
      rapamycin treatment on Treg cell function. RESULTS: SLE Treg cells exhibited 
      increased activities of mTORC1 and mTORC2, whereas autophagy, the expression of 
      GATA-3 and CTLA-4, and the suppressor function of Treg cells were diminished. 
      IL-21, but not IL-6 or IL-17, blocked the development of Treg cells. IL-21 
      stimulated mTORC1 and mTORC2, and it abrogated the autophagy, differentiation, 
      and function of Treg cells. Moreover, IL-21 constrained the expression of GATA-3 
      and CTLA-4 selectively in Treg cells. In turn, blockade of mTORC1 by 3-day 
      rapamycin treatment enhanced transforming growth factor beta production, while dual 
      blockade of mTORC1 and mTORC2 by 4-week rapamycin treatment induced autophagy, 
      restored the expression of GATA-3 and CTLA-4, and corrected Treg cell function. 
      CONCLUSION: IL-21-driven mTOR activation is a pharmacologically targetable 
      checkpoint of the deficient autophagy that underlies Treg cell dysfunction in 
      SLE.
CI  - (c) 2017, American College of Rheumatology.
FAU - Kato, Hiroshi
AU  - Kato H
AD  - State University of New York, Syracuse.
FAU - Perl, Andras
AU  - Perl A
AD  - State University of New York, Syracuse.
LA  - eng
GR  - R01 AI048079/AI/NIAID NIH HHS/United States
GR  - R01 AI072648/AI/NIAID NIH HHS/United States
GR  - R01 AI122176/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 - 20180130
PL  - United States
TA  - Arthritis Rheumatol
JT  - Arthritis & rheumatology (Hoboken, N.J.)
JID - 101623795
RN  - 0 (Interleukins)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - MKM3CA6LT1 (interleukin-21)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adult
MH  - Autophagy/drug effects
MH  - Cell Differentiation/drug effects
MH  - Female
MH  - Flow Cytometry
MH  - Humans
MH  - Immunoblotting
MH  - Interleukins/*pharmacology
MH  - Lupus Erythematosus, Systemic/drug therapy/*metabolism
MH  - Male
MH  - Middle Aged
MH  - Signal Transduction
MH  - Sirolimus/*pharmacology
MH  - T-Lymphocytes, Regulatory/*drug effects/metabolism
MH  - TOR Serine-Threonine Kinases/*metabolism
PMC - PMC5826851
MID - NIHMS921073
COIS- The authors declare no competing financial interests.
EDAT- 2017/11/22 06:00
MHDA- 2019/01/12 06:00
PMCR- 2019/03/01
CRDT- 2017/11/22 06:00
PHST- 2017/10/02 00:00 [received]
PHST- 2017/11/14 00:00 [accepted]
PHST- 2017/11/22 06:00 [pubmed]
PHST- 2019/01/12 06:00 [medline]
PHST- 2017/11/22 06:00 [entrez]
PHST- 2019/03/01 00:00 [pmc-release]
AID - 10.1002/art.40380 [doi]
PST - ppublish
SO  - Arthritis Rheumatol. 2018 Mar;70(3):427-438. doi: 10.1002/art.40380. Epub 2018 
      Jan 30.