PMID- 30129283
OWN - NLM
STAT- MEDLINE
DCOM- 20200713
LR  - 20230124
IS  - 1600-6143 (Electronic)
IS  - 1600-6135 (Print)
IS  - 1600-6135 (Linking)
VI  - 19
IP  - 3
DP  - 2019 Mar
TI  - mTORC2 deficiency in cutaneous dendritic cells potentiates CD8(+) effector T cell 
      responses and accelerates skin graft rejection.
PG  - 646-661
LID - 10.1111/ajt.15083 [doi]
AB  - Mechanistic target of rapamycin (mTOR) complex (mTORC)1 and mTORC2 regulate the 
      differentiation and function of immune cells. While inhibition of mTORC1 
      antagonizes dendritic cell (DC) differentiation and suppresses graft rejection, 
      the role of mTORC2 in DCs in determining host responses to transplanted tissue 
      remains undefined. Using a mouse model in which mTORC2 was deleted specifically 
      in CD11c(+) DCs (TORC2(DC-/-) ), we show that the transplant of minor 
      histocompatibility Ag (HY)-mismatched skin grafts from TORC2(DC-/-) donors into 
      wild-type recipients results in accelerated rejection characterized by enhanced 
      CD8(+) T cell responses in the graft and regional lymphoid tissue [Correction 
      added on January 9, 2019, after first online publication: in the previous 
      sentence, major was changed to minor]. Similar enhancement of CD8(+) effector T 
      cell responses was observed in MHC-mismatched recipients of TORC2(DC-/-) grafts. 
      Augmented CD8(+) T cell responses were also observed in a delayed-type 
      hypersensitivity model in which mTORC2 was absent in cutaneous DCs. These 
      elevated responses could be ascribed to an increased T cell stimulatory phenotype 
      of TORC2(DC-/-) and not to enhanced lymph node homing of the cells. In contrast, 
      rejection of ovalbumin transgenic skin grafts in TORC2(DC-/-) recipients was 
      unaffected. These findings suggest that mTORC2 in skin DCs restrains effector 
      CD8(+) T cell responses and have implications for understanding of the influence 
      of mTOR inhibitors that target mTORC2 in transplant.
CI  - (c) 2018 The American Society of Transplantation and the American Society of 
      Transplant Surgeons.
FAU - Watson, Alicia R
AU  - Watson AR
AD  - Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh 
      School of Medicine, Pittsburgh, PA, USA.
AD  - Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, 
      PA, USA.
FAU - Dai, Helong
AU  - Dai H
AD  - Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh 
      School of Medicine, Pittsburgh, PA, USA.
AD  - Department of Urological Organ Transplantation, The Second Xiangya Hospital of 
      Central South University, Changsha, China.
FAU - Diaz-Perez, Julio A
AU  - Diaz-Perez JA
AD  - Department of Dermatology, University of Pittsburgh School of Medicine, 
      Pittsburgh, PA, USA.
FAU - Killeen, Meaghan E
AU  - Killeen ME
AD  - Department of Dermatology, University of Pittsburgh School of Medicine, 
      Pittsburgh, PA, USA.
FAU - Mathers, Alicia R
AU  - Mathers AR
AD  - Department of Dermatology, University of Pittsburgh School of Medicine, 
      Pittsburgh, PA, USA.
AD  - Department of Immunology, University of Pittsburgh School of Medicine, 
      Pittsburgh, PA, USA.
FAU - Thomson, Angus W
AU  - Thomson AW
AD  - Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh 
      School of Medicine, Pittsburgh, PA, USA.
AD  - Department of Immunology, University of Pittsburgh School of Medicine, 
      Pittsburgh, PA, USA.
LA  - eng
GR  - R01 AR067746/AR/NIAMS NIH HHS/United States
GR  - T32 AI074490/AI/NIAID NIH HHS/United States
GR  - R01 AI118777/AI/NIAID NIH HHS/United States
GR  - R01 AI067541/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20180917
PL  - United States
TA  - Am J Transplant
JT  - American journal of transplantation : official journal of the American Society of 
      Transplantation and the American Society of Transplant Surgeons
JID - 100968638
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
SB  - IM
MH  - Animals
MH  - CD8-Positive T-Lymphocytes/*immunology/metabolism/pathology
MH  - Dendritic Cells/*immunology/metabolism/pathology
MH  - Female
MH  - Graft Rejection/*etiology/metabolism/pathology
MH  - Graft Survival
MH  - Lymphocyte Activation/*immunology
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 2/*physiology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Skin/*immunology/metabolism/pathology
MH  - Skin Transplantation/*adverse effects
PMC - PMC6384165
MID - NIHMS986342
OTO - NOTNLM
OT  - antigen presentation/recognition
OT  - basic (laboratory) research/science
OT  - cellular biology
OT  - dendritic cell
OT  - dermatology
OT  - immunobiology
OT  - immunosuppressant - mechanistic target of rapamycin (mTOR)
EDAT- 2018/08/22 06:00
MHDA- 2020/07/14 06:00
PMCR- 2020/03/01
CRDT- 2018/08/22 06:00
PHST- 2018/03/23 00:00 [received]
PHST- 2018/07/27 00:00 [revised]
PHST- 2018/08/14 00:00 [accepted]
PHST- 2018/08/22 06:00 [pubmed]
PHST- 2020/07/14 06:00 [medline]
PHST- 2018/08/22 06:00 [entrez]
PHST- 2020/03/01 00:00 [pmc-release]
AID - S1600-6135(22)08980-8 [pii]
AID - 10.1111/ajt.15083 [doi]
PST - ppublish
SO  - Am J Transplant. 2019 Mar;19(3):646-661. doi: 10.1111/ajt.15083. Epub 2018 Sep 
      17.