PMID- 27402696
OWN - NLM
STAT- MEDLINE
DCOM- 20170802
LR  - 20211204
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 197
IP  - 4
DP  - 2016 Aug 15
TI  - A Novel mTORC1-Dependent, Akt-Independent Pathway Differentiates the Gut Tropism 
      of Regulatory and Conventional CD4 T Cells.
PG  - 1137-47
LID - 10.4049/jimmunol.1600696 [doi]
AB  - The vitamin A metabolite all-trans retinoic acid (ATRA) induces a gut-homing 
      phenotype in activated CD4(+) conventional T cells (Tconv) by upregulating the 
      integrin alpha4beta7 and the chemokine receptor CCR9. We report that, in contrast to 
      mouse Tconv, only  approximately 50% of regulatory T cells (Treg) upregulate CCR9 when 
      stimulated by physiological levels of ATRA, even though Tconv and Treg express 
      similar levels of the retinoic acid receptor (RAR). The resulting bimodal CCR9 
      expression is not associated with differences in the extent of their 
      proliferation, level of Foxp3 expression, or affiliation with naturally occurring 
      Treg or induced Treg in the circulating Treg pool. Furthermore, we find that 
      exposure of Treg to the mechanistic target of rapamycin (mTOR) inhibitor 
      rapamycin suppresses upregulation of both CCR9 and alpha4beta7, an effect that is not 
      evident with Tconv. This suggests that in Treg, ATRA-induced upregulation of CCR9 
      and alpha4beta7 is dependent on activation of a mTOR signaling pathway. The involvement 
      of mTOR is independent of Akt activity, because specific inhibition of Akt, 
      pyruvate dehydrogenase kinase-1, or its downstream target glycogen synthase 
      kinase-3 did not prevent CCR9 expression. Additionally, Rictor (mTOR complex 
      [mTORC]2)-deficient Treg showed unaltered ability to express CCR9, whereas Raptor 
      (mTORC1)-deficient Treg were unable to upregulate CCR9, suggesting the selective 
      participation of mTORC1. These findings reveal a novel difference between ATRA 
      signaling and chemokine receptor induction in Treg versus Tconv and provide a 
      framework via which the migratory behavior of Treg versus Tconv might be 
      regulated differentially for therapeutic purposes.
CI  - Copyright (c) 2016 by The American Association of Immunologists, Inc.
FAU - Chen, Leo C
AU  - Chen LC
AD  - Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh 
      School of Medicine, Pittsburgh, PA 15213; and.
FAU - Nicholson, Yawah T
AU  - Nicholson YT
AUID- ORCID: 0000-0002-6834-7006
AD  - Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh 
      School of Medicine, Pittsburgh, PA 15213; and.
FAU - Rosborough, Brian R
AU  - Rosborough BR
AD  - Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh 
      School of Medicine, Pittsburgh, PA 15213; and.
FAU - Thomson, Angus W
AU  - Thomson AW
AUID- ORCID: 0000-0001-6731-8871
AD  - Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh 
      School of Medicine, Pittsburgh, PA 15213; and Department of Immunology, 
      University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 
      g.raimondi@jhmi.edu thomsonaw@upmc.edu.
FAU - Raimondi, Giorgio
AU  - Raimondi G
AD  - Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh 
      School of Medicine, Pittsburgh, PA 15213; and g.raimondi@jhmi.edu 
      thomsonaw@upmc.edu.
LA  - eng
GR  - R01 AI067541/AI/NIAID NIH HHS/United States
GR  - UL1 TR000005/TR/NCATS NIH HHS/United States
GR  - HHMI/Howard Hughes Medical Institute/United States
PT  - Journal Article
DEP - 20160711
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (CC chemokine receptor 9)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Receptors, CCR)
RN  - 5688UTC01R (Tretinoin)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - CD4-Positive T-Lymphocytes/drug effects/*immunology/metabolism
MH  - Cell Separation
MH  - Chemotaxis, Leukocyte/drug effects/*immunology
MH  - Flow Cytometry
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Multiprotein Complexes/*metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Receptors, CCR/biosynthesis
MH  - Signal Transduction/physiology
MH  - T-Lymphocytes, Regulatory/drug effects/*immunology/metabolism
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Tretinoin/pharmacology
PMC - PMC4975979
MID - NIHMS795008
EDAT- 2016/07/13 06:00
MHDA- 2017/08/03 06:00
PMCR- 2017/08/15
CRDT- 2016/07/13 06:00
PHST- 2016/04/20 00:00 [received]
PHST- 2016/06/08 00:00 [accepted]
PHST- 2016/07/13 06:00 [entrez]
PHST- 2016/07/13 06:00 [pubmed]
PHST- 2017/08/03 06:00 [medline]
PHST- 2017/08/15 00:00 [pmc-release]
AID - jimmunol.1600696 [pii]
AID - 10.4049/jimmunol.1600696 [doi]
PST - ppublish
SO  - J Immunol. 2016 Aug 15;197(4):1137-47. doi: 10.4049/jimmunol.1600696. Epub 2016 
      Jul 11.