PMID- 29133782
OWN - NLM
STAT- MEDLINE
DCOM- 20180911
LR  - 20230810
IS  - 2041-1723 (Electronic)
IS  - 2041-1723 (Linking)
VI  - 8
IP  - 1
DP  - 2017 Nov 13
TI  - mTOR intersects antibody-inducing signals from TACI in marginal zone B cells.
PG  - 1462
LID - 10.1038/s41467-017-01602-4 [doi]
LID - 1462
AB  - Mechanistic target of rapamycin (mTOR) enhances immunity in addition to 
      orchestrating metabolism. Here we show that mTOR coordinates immunometabolic 
      reconfiguration of marginal zone (MZ) B cells, a pre-activated lymphocyte subset 
      that mounts antibody responses to T-cell-independent antigens through a Toll-like 
      receptor (TLR)-amplified pathway involving transmembrane activator and CAML 
      interactor (TACI). This receptor interacts with mTOR via the TLR adapter MyD88. 
      The resulting mTOR activation instigates MZ B-cell proliferation, immunoglobulin 
      G (IgG) class switching, and plasmablast differentiation through a 
      rapamycin-sensitive pathway that integrates metabolic and antibody-inducing 
      transcription programs, including NF-kappaB. Disruption of TACI-mTOR interaction by 
      rapamycin, truncation of the MyD88-binding domain of TACI, or B-cell-conditional 
      mTOR deficiency interrupts TACI signaling via NF-kappaB and cooperation with TLRs, 
      thereby hampering IgG production to T-cell-independent antigens but not B-cell 
      survival. Thus, mTOR drives innate-like antibody responses by linking proximal 
      TACI signaling events with distal immunometabolic transcription programs.
FAU - Sintes, Jordi
AU  - Sintes J
AD  - Program for Inflammatory and Cardiovascular Disorders, Institut Hospital del Mar 
      d'Investigacions Mediques (IMIM), Barcelona, 08003, Spain. jsintes@imim.es.
FAU - Gentile, Maurizio
AU  - Gentile M
AD  - Program for Inflammatory and Cardiovascular Disorders, Institut Hospital del Mar 
      d'Investigacions Mediques (IMIM), Barcelona, 08003, Spain.
FAU - Zhang, Shuling
AU  - Zhang S
AD  - Laboratory of Cancer Biology and Genetics, National Cancer Institute, National 
      Institutes of Health, Bethesda, MD, 20892, USA.
FAU - Garcia-Carmona, Yolanda
AU  - Garcia-Carmona Y
AD  - Department of Medicine and Pediatrics, Immunology Institute, Icahn School of 
      Medicine at Mount Sinai, New York, NY, 10029, USA.
FAU - Magri, Giuliana
AU  - Magri G
AD  - Program for Inflammatory and Cardiovascular Disorders, Institut Hospital del Mar 
      d'Investigacions Mediques (IMIM), Barcelona, 08003, Spain.
FAU - Cassis, Linda
AU  - Cassis L
AD  - Program for Inflammatory and Cardiovascular Disorders, Institut Hospital del Mar 
      d'Investigacions Mediques (IMIM), Barcelona, 08003, Spain.
FAU - Segura-Garzon, Daniel
AU  - Segura-Garzon D
AD  - Program for Inflammatory and Cardiovascular Disorders, Institut Hospital del Mar 
      d'Investigacions Mediques (IMIM), Barcelona, 08003, Spain.
FAU - Ciociola, Alessandra
AU  - Ciociola A
AD  - Program for Inflammatory and Cardiovascular Disorders, Institut Hospital del Mar 
      d'Investigacions Mediques (IMIM), Barcelona, 08003, Spain.
FAU - Grasset, Emilie K
AU  - Grasset EK
AD  - Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount 
      Sinai, New York, NY, 10029, USA.
AD  - Department of Medicine, Center for Molecular Medicine at Karolinska University 
      Hospital, Karolinska Institutet, Stockholm, 171 76, Sweden.
FAU - Bascones, Sabrina
AU  - Bascones S
AD  - Program for Inflammatory and Cardiovascular Disorders, Institut Hospital del Mar 
      d'Investigacions Mediques (IMIM), Barcelona, 08003, Spain.
FAU - Comerma, Laura
AU  - Comerma L
AD  - Program for Inflammatory and Cardiovascular Disorders, Institut Hospital del Mar 
      d'Investigacions Mediques (IMIM), Barcelona, 08003, Spain.
FAU - Pybus, Marc
AU  - Pybus M
AD  - Program for Inflammatory and Cardiovascular Disorders, Institut Hospital del Mar 
      d'Investigacions Mediques (IMIM), Barcelona, 08003, Spain.
FAU - Llige, David
AU  - Llige D
AD  - Program for Inflammatory and Cardiovascular Disorders, Institut Hospital del Mar 
      d'Investigacions Mediques (IMIM), Barcelona, 08003, Spain.
FAU - Puga, Irene
AU  - Puga I
AD  - Program for Inflammatory and Cardiovascular Disorders, Institut Hospital del Mar 
      d'Investigacions Mediques (IMIM), Barcelona, 08003, Spain.
FAU - Gutzeit, Cindy
AU  - Gutzeit C
AD  - Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount 
      Sinai, New York, NY, 10029, USA.
FAU - He, Bing
AU  - He B
AD  - Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount 
      Sinai, New York, NY, 10029, USA.
FAU - DuBois, Wendy
AU  - DuBois W
AD  - Laboratory of Cancer Biology and Genetics, National Cancer Institute, National 
      Institutes of Health, Bethesda, MD, 20892, USA.
FAU - Crespo, Marta
AU  - Crespo M
AD  - Department of Nephrology, Institut Hospital del Mar d'Investigacions Mediques 
      (IMIM), Barcelona, 08003, Spain.
FAU - Pascual, Julio
AU  - Pascual J
AD  - Department of Nephrology, Institut Hospital del Mar d'Investigacions Mediques 
      (IMIM), Barcelona, 08003, Spain.
FAU - Mensa, Anna
AU  - Mensa A
AD  - Immunology Service, Hospital Clinic of Barcelona, Barcelona, 08036, Spain.
FAU - Arostegui, Juan Ignacio
AU  - Arostegui JI
AD  - Immunology Service, Hospital Clinic of Barcelona, Barcelona, 08036, Spain.
FAU - Juan, Manel
AU  - Juan M
AUID- ORCID: 0000-0002-3064-1648
AD  - Immunology Service, Hospital Clinic of Barcelona, Barcelona, 08036, Spain.
FAU - Yague, Jordi
AU  - Yague J
AD  - Immunology Service, Hospital Clinic of Barcelona, Barcelona, 08036, Spain.
FAU - Serrano, Sergi
AU  - Serrano S
AD  - Department of Pathology, Hospital del Mar, Barcelona, 08003, Spain.
AD  - Universitat Pompeu Fabra, Barcelona, 08003, Spain.
FAU - Lloreta, Josep
AU  - Lloreta J
AD  - Department of Pathology, Hospital del Mar, Barcelona, 08003, Spain.
AD  - Universitat Pompeu Fabra, Barcelona, 08003, Spain.
FAU - Meffre, Eric
AU  - Meffre E
AD  - Department of Immunobiology, Yale University, New Haven, CT, 06511, USA.
FAU - Hahne, Michael
AU  - Hahne M
AD  - Molecular Genetics Institute of Montpellier, Montpellier, 34293, France.
FAU - Cunningham-Rundles, Charlotte
AU  - Cunningham-Rundles C
AD  - Department of Medicine and Pediatrics, Immunology Institute, Icahn School of 
      Medicine at Mount Sinai, New York, NY, 10029, USA.
FAU - Mock, Beverly A
AU  - Mock BA
AUID- ORCID: 0000-0003-2479-4549
AD  - Laboratory of Cancer Biology and Genetics, National Cancer Institute, National 
      Institutes of Health, Bethesda, MD, 20892, USA.
FAU - Cerutti, Andrea
AU  - Cerutti A
AD  - Program for Inflammatory and Cardiovascular Disorders, Institut Hospital del Mar 
      d'Investigacions Mediques (IMIM), Barcelona, 08003, Spain. acerutti@imim.es.
AD  - Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount 
      Sinai, New York, NY, 10029, USA. acerutti@imim.es.
AD  - Catalan Institute for Research and Advanced Studies (ICREA), Barcelona, 08003, 
      Spain. acerutti@imim.es.
LA  - eng
GR  - P01 AI061093/AI/NIAID NIH HHS/United States
GR  - R01 AI057653/AI/NIAID NIH HHS/United States
GR  - U01 AI095613/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 - 20171113
PL  - England
TA  - Nat Commun
JT  - Nature communications
JID - 101528555
RN  - 0 (Immunoglobulin G)
RN  - 0 (MYD88 protein, human)
RN  - 0 (Myeloid Differentiation Factor 88)
RN  - 0 (NF-kappa B)
RN  - 0 (TNFRSF13B protein, human)
RN  - 0 (Transmembrane Activator and CAML Interactor Protein)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - B-Lymphocytes/*immunology
MH  - Cell Line
MH  - Cell Proliferation
MH  - Enzyme Activation
MH  - Gene Expression Profiling
MH  - HEK293 Cells
MH  - Humans
MH  - Immunoglobulin Class Switching/genetics/immunology
MH  - Immunoglobulin G/biosynthesis/*immunology
MH  - Lymphocyte Activation/immunology
MH  - Mechanistic Target of Rapamycin Complex 1/*immunology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Myeloid Differentiation Factor 88/*metabolism
MH  - NF-kappa B/metabolism
MH  - Signal Transduction/immunology
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/*immunology
MH  - Transmembrane Activator and CAML Interactor Protein/*immunology
PMC - PMC5684130
COIS- The authors declare no competing financial interests.
EDAT- 2017/11/15 06:00
MHDA- 2018/09/12 06:00
PMCR- 2017/11/13
CRDT- 2017/11/15 06:00
PHST- 2016/12/14 00:00 [received]
PHST- 2017/10/03 00:00 [accepted]
PHST- 2017/11/15 06:00 [entrez]
PHST- 2017/11/15 06:00 [pubmed]
PHST- 2018/09/12 06:00 [medline]
PHST- 2017/11/13 00:00 [pmc-release]
AID - 10.1038/s41467-017-01602-4 [pii]
AID - 1602 [pii]
AID - 10.1038/s41467-017-01602-4 [doi]
PST - epublish
SO  - Nat Commun. 2017 Nov 13;8(1):1462. doi: 10.1038/s41467-017-01602-4.