PMID- 21253614
OWN - NLM
STAT- MEDLINE
DCOM- 20110802
LR  - 20220311
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 6
IP  - 1
DP  - 2011 Jan 6
TI  - Ncf1 (p47phox) is essential for direct regulatory T cell mediated suppression of 
      CD4+ effector T cells.
PG  - e16013
LID - 10.1371/journal.pone.0016013 [doi]
LID - e16013
AB  - BACKGROUND: Multiple mechanisms have been advanced to account for CD4+FOXP3+ 
      regulatory T cell (Treg)-mediated suppression of CD4+ effector T cells (Teffs) 
      but none appear to completely explain suppression. Previous data indicates that 
      Tregs may affect the microenvironment redox state. Given the inherent redox 
      sensitivity of T cells, we tested the hypothesis that oxidants may mediate the 
      direct suppression of Teffs by Tregs. METHODOLOGY/PRINCIPAL FINDINGS: Tregs and 
      Teffs were isolated from the spleens of wild type (WT) C57BL/6 mice or 
      Ncf1(p47phox)-deficient C57BL/6 mice which lack NADPH oxidase function. Teffs 
      were labeled with CFSE and co-cultured with unlabeled Tregs at varying Treg:Teff 
      ratios in the presence of anti-CD3/CD28 coated beads for 3 days in suppression 
      assays. Treg-mediated suppression was quantified by flow cytometric analysis of 
      CFSE dilution in Teffs. The presence of the antioxidants n-acetylcysteine (NAC) 
      or 2-mercaptoethanol or inhibitors of NADPH oxidase (diphenyleneiodonium and 
      VAS-2870) resulted in reduced WT Treg-mediated suppression. The observed 
      suppression was in part dependent upon TGFbeta as it was partially blocked with 
      neutralizing antibodies. The suppression of Teff proliferation induced by 
      exogenous TGFbeta treatment could be overcome with NAC. Ncf1-deficient Teff were 
      slightly but significantly less sensitive than WT Teff to suppression by 
      exogenous TGFbeta. Ncf1-deficient Tregs suppressed Ncf1-deficient Teff very poorly 
      compared to wild type controls. There was partial but incomplete reconstitution 
      of suppression in assays with WT Tregs and Ncf1-deficient Teff. 
      CONCLUSIONS/SIGNIFICANCE: We present evidence that NADPH oxidase derived ROS 
      plays a role in the direct Treg mediated suppression of CD4+ effector T cells in 
      a process that is blocked by thiol-containing antioxidants, NADPH oxidase 
      inhibitors or a lack of Ncf1 expression in Tregs and Teffs. Oxidants may 
      represent a potential new target for therapeutic modulation of Treg function.
FAU - Efimova, Olga
AU  - Efimova O
AD  - Department of Pathology, University of Utah, Salt Lake City, Utah, United States 
      of America.
FAU - Szankasi, Philippe
AU  - Szankasi P
FAU - Kelley, Todd W
AU  - Kelley TW
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110106
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antioxidants)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Sulfhydryl Compounds)
RN  - 0 (Transforming Growth Factor beta)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 1.6.3.1 (neutrophil cytosolic factor 1)
SB  - IM
MH  - Animals
MH  - Antioxidants/*pharmacology
MH  - CD4-Positive T-Lymphocytes/*immunology
MH  - Cell Proliferation
MH  - Immune System Phenomena
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - NADPH Oxidases/deficiency/*physiology
MH  - Reactive Oxygen Species
MH  - Sulfhydryl Compounds/pharmacology
MH  - T-Lymphocytes, Regulatory/*immunology
MH  - Transforming Growth Factor beta/pharmacology
PMC - PMC3017100
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2011/01/22 06:00
MHDA- 2011/08/04 06:00
PMCR- 2011/01/06
CRDT- 2011/01/22 06:00
PHST- 2010/09/06 00:00 [received]
PHST- 2010/12/02 00:00 [accepted]
PHST- 2011/01/22 06:00 [entrez]
PHST- 2011/01/22 06:00 [pubmed]
PHST- 2011/08/04 06:00 [medline]
PHST- 2011/01/06 00:00 [pmc-release]
AID - PONE-D-10-01695 [pii]
AID - 10.1371/journal.pone.0016013 [doi]
PST - epublish
SO  - PLoS One. 2011 Jan 6;6(1):e16013. doi: 10.1371/journal.pone.0016013.