PMID- 32386462
OWN - NLM
STAT- MEDLINE
DCOM- 20210617
LR  - 20211204
IS  - 1742-4658 (Electronic)
IS  - 1742-464X (Print)
IS  - 1742-464X (Linking)
VI  - 288
IP  - 2
DP  - 2021 Jan
TI  - Attenuation of canonical NF-kappaB signaling maintains function and stability of 
      human Treg.
PG  - 640-662
LID - 10.1111/febs.15361 [doi]
AB  - Nuclear factor 'kappa-light-chain-enhancer' of activated B cells (NF-kappaB) signaling is 
      a signaling pathway used by most immune cells to promote immunostimulatory 
      functions. Recent studies have indicated that regulatory T cells (Treg) 
      differentially integrate TCR-derived signals, thereby maintaining their 
      suppressive features. However, the role of NF-kappaB signaling in the activation of 
      human peripheral blood (PB) Treg has not been fully elucidated so far. We show 
      that the activity of the master transcription factor forkhead box protein 3 
      (FOXP3) attenuates p65 phosphorylation and nuclear translocation of the NF-kappaB 
      proteins p50, p65, and c-Rel following activation in human Treg. Using 
      pharmacological and genetic inhibition of canonical NF-kappaB signaling in 
      FOXP3-transgenic T cells and PB Treg from healthy donors as well as Treg from a 
      patient with a primary NFKB1 haploinsufficiency, we validate that Treg activation 
      and suppressive capacity is independent of NF-kappaB signaling. Additionally, 
      repression of residual NF-kappaB signaling in Treg further enhances interleukin-10 
      (IL-10) production. Blockade of NF-kappaB signaling can be exploited for the 
      generation of in vitro induced Treg (iTreg) with enhanced suppressive capacity 
      and functional stability. In this respect, dual blockade of mammalian target of 
      rapamycin (mTOR) and NF-kappaB signaling was accompanied by enhanced expression of 
      the transcription factors FOXP1 and FOXP3 and demethylation of the Treg-specific 
      demethylated region compared to iTreg generated under mTOR blockade alone. Thus, 
      we provide first insights into the role of NF-kappaB signaling in human Treg. These 
      findings could lead to strategies for the selective manipulation of Treg and the 
      generation of improved iTreg for cellular therapy.
CI  - (c) 2020 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf 
      of Federation of European Biochemical Societies.
FAU - Ziegler, Liesa S
AU  - Ziegler LS
AD  - Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
FAU - Gerner, Marlene C
AU  - Gerner MC
AUID- ORCID: 0000-0002-4378-9254
AD  - Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
FAU - Schmidt, Ralf L J
AU  - Schmidt RLJ
AD  - Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
FAU - Trapin, Doris
AU  - Trapin D
AD  - Institute of Immunology, Medical University of Vienna, Vienna, Austria.
FAU - Steinberger, Peter
AU  - Steinberger P
AD  - Institute of Immunology, Medical University of Vienna, Vienna, Austria.
FAU - Pickl, Winfried F
AU  - Pickl WF
AD  - Institute of Immunology, Medical University of Vienna, Vienna, Austria.
FAU - Sillaber, Christian
AU  - Sillaber C
AD  - Division of Hematology and Hemostaseology, Department of Internal Medicine I, 
      Medical University of Vienna, Vienna, Austria.
FAU - Egger, Gerda
AU  - Egger G
AD  - Department of Pathology, Medical University of Vienna, Vienna, Austria.
AD  - Ludwig Boltzmann Institute Applied Diagnostics, Vienna, Austria.
FAU - Schwarzinger, Ilse
AU  - Schwarzinger I
AD  - Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
FAU - Schmetterer, Klaus G
AU  - Schmetterer KG
AUID- ORCID: 0000-0001-9328-4871
AD  - Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
LA  - eng
GR  - P 29654/FWF_/Austrian Science Fund FWF/Austria
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200528
PL  - England
TA  - FEBS J
JT  - The FEBS journal
JID - 101229646
RN  - 0 (FOXP1 protein, human)
RN  - 0 (FOXP3 protein, human)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (IL10 protein, human)
RN  - 0 (NF-kappa B p50 Subunit)
RN  - 0 (RELA protein, human)
RN  - 0 (Repressor Proteins)
RN  - 0 (Thiazoles)
RN  - 0 (Transcription Factor RelA)
RN  - 130068-27-8 (Interleukin-10)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Active Transport, Cell Nucleus/drug effects/immunology
MH  - Cell Nucleus/drug effects/immunology/metabolism
MH  - Forkhead Transcription Factors/genetics/*immunology
MH  - Gene Expression Regulation
MH  - Haploinsufficiency/*immunology
MH  - Humans
MH  - Interleukin-10/genetics/immunology
MH  - Lymphocyte Activation
MH  - NF-kappa B p50 Subunit/deficiency/genetics/*immunology
MH  - Phosphorylation/drug effects
MH  - Primary Cell Culture
MH  - Repressor Proteins/genetics/immunology
MH  - Signal Transduction
MH  - Sirolimus/pharmacology
MH  - T-Lymphocytes, Regulatory/cytology/drug effects/*immunology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/genetics/*immunology
MH  - Thiazoles/pharmacology
MH  - Transcription Factor RelA/antagonists & inhibitors/genetics/*immunology
PMC - PMC7891634
OTO - NOTNLM
OT  - NF-kappaB signaling
OT  - TSDR
OT  - immune tolerance
OT  - regulatory T cells
COIS- The authors declare no conflict of interest.
EDAT- 2020/05/10 06:00
MHDA- 2021/06/22 06:00
PMCR- 2021/02/18
CRDT- 2020/05/10 06:00
PHST- 2019/08/14 00:00 [received]
PHST- 2020/02/07 00:00 [revised]
PHST- 2020/05/05 00:00 [accepted]
PHST- 2020/05/10 06:00 [pubmed]
PHST- 2021/06/22 06:00 [medline]
PHST- 2020/05/10 06:00 [entrez]
PHST- 2021/02/18 00:00 [pmc-release]
AID - FEBS15361 [pii]
AID - 10.1111/febs.15361 [doi]
PST - ppublish
SO  - FEBS J. 2021 Jan;288(2):640-662. doi: 10.1111/febs.15361. Epub 2020 May 28.