PMID- 18635688
OWN - NLM
STAT- MEDLINE
DCOM- 20080819
LR  - 20211020
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 105
IP  - 29
DP  - 2008 Jul 22
TI  - Foxp3+ natural regulatory T cells preferentially form aggregates on dendritic 
      cells in vitro and actively inhibit their maturation.
PG  - 10113-8
LID - 10.1073/pnas.0711106105 [doi]
AB  - Naturally occurring CD4(+)CD25(+) regulatory T cells (Treg) suppress in vitro the 
      proliferation of other T cells in a cell-contact-dependent manner. Dendritic 
      cells (DCs) appear to be a target of Treg-mediated immune suppression. We show 
      here that, in coculture of dye-labeled Treg cells and CD4(+)CD25(-) naive T cells 
      in the presence of T cell receptor stimulation, Treg cells, which are more mobile 
      than naive T cells in vitro, out-compete the latter in aggregating around DCs. 
      Deficiency or blockade of leukocyte function-associated antigen-1 (LFA-1) 
      (CD11a/CD18) abrogates Treg aggregation, whereas that of cytotoxic T 
      lymphocyte-associated antigen 4 (CTLA-4) (CD152) does not. After forming 
      aggregates, Treg cells specifically down-regulate the expression of CD80/86, but 
      not CD40 or class II MHC, on DCs in both a CTLA-4- and LFA-1-dependent manner. 
      Notably, Treg exerts this CD80/86-down-modulating effect even in the presence of 
      strong DC-maturating stimuli, such as GM-CSF, TNF-alpha, IFN-gamma, type I IFN, 
      and lipopolysaccharide. Taken together, as a possible mechanism of in vitro 
      Treg-mediated cell contact-dependent suppression, we propose that 
      antigen-activated Treg cells exert suppression by two distinct steps: initial 
      LFA-1-dependent formation of Treg aggregates on immature DCs and subsequent 
      LFA-1- and CTLA-4-dependent active down-modulation of CD80/86 expression on DCs. 
      Both steps prevent antigen-reactive naive T cells from being activated by 
      antigen-presenting DCs, resulting in specific immune suppression and tolerance.
FAU - Onishi, Yasushi
AU  - Onishi Y
AD  - Department of Experimental Pathology, Institute for Frontier Medical Sciences, 
      Kyoto University, Kyoto 606-8507, Japan.
FAU - Fehervari, Zoltan
AU  - Fehervari Z
FAU - Yamaguchi, Tomoyuki
AU  - Yamaguchi T
FAU - Sakaguchi, Shimon
AU  - Sakaguchi S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080717
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Antigens, CD)
RN  - 0 (B7-1 Antigen)
RN  - 0 (B7-2 Antigen)
RN  - 0 (CTLA-4 Antigen)
RN  - 0 (Cd86 protein, mouse)
RN  - 0 (Ctla4 protein, mouse)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Foxp3 protein, mouse)
RN  - 0 (Lymphocyte Function-Associated Antigen-1)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 9006-59-1 (Ovalbumin)
SB  - IM
MH  - Animals
MH  - Antigens, CD/genetics/immunology/metabolism
MH  - B7-1 Antigen/metabolism
MH  - B7-2 Antigen/metabolism
MH  - CTLA-4 Antigen
MH  - Cell Aggregation
MH  - Cell Differentiation
MH  - Dendritic Cells/*cytology/*immunology/metabolism
MH  - Female
MH  - Forkhead Transcription Factors/*metabolism
MH  - Lymphocyte Function-Associated Antigen-1/genetics/immunology/metabolism
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - Models, Immunological
MH  - Ovalbumin/genetics/immunology
MH  - Receptors, Antigen, T-Cell/genetics/metabolism
MH  - T-Lymphocytes, Regulatory/*cytology/*immunology/metabolism
PMC - PMC2481354
COIS- The authors declare no conflict of interest.
EDAT- 2008/07/19 09:00
MHDA- 2008/08/20 09:00
PMCR- 2009/01/22
CRDT- 2008/07/19 09:00
PHST- 2008/07/19 09:00 [pubmed]
PHST- 2008/08/20 09:00 [medline]
PHST- 2008/07/19 09:00 [entrez]
PHST- 2009/01/22 00:00 [pmc-release]
AID - 0711106105 [pii]
AID - 3476 [pii]
AID - 10.1073/pnas.0711106105 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):10113-8. doi: 
      10.1073/pnas.0711106105. Epub 2008 Jul 17.