PMID- 21602513
OWN - NLM
STAT- MEDLINE
DCOM- 20110829
LR  - 20220330
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 60
IP  - 7
DP  - 2011 Jul
TI  - The soluble CTLA-4 splice variant protects from type 1 diabetes and potentiates 
      regulatory T-cell function.
PG  - 1955-63
LID - 10.2337/db11-0130 [doi]
AB  - OBJECTIVE: CTLA4 gene variation associates with multiple autoimmune disorders, 
      including type 1 diabetes. The CTLA4 susceptibility allele was found to generate 
      decreased levels of mRNA encoding soluble CTLA-4 (sCTLA-4) relative to the 
      full-length isoform, the functional consequence of which is as yet unknown. In 
      this study, we investigated the contribution of sCTLA-4 to immune regulation with 
      the aim to elucidate the functional basis of the disease association of CTLA4. 
      RESEARCH DESIGN AND METHODS: To model the disease-associated splicing variation 
      of CTLA4, we generated NOD mice in which sCTLA-4 mRNA is silenced by RNA 
      interference. RESULTS: We found that loss of sCTLA-4 impairs the function of 
      regulatory T (Treg) cells. This functional defect could be attributed, at least 
      in part, to the failure of sCTLA-4 knockdown (KD) Treg cells to downregulate 
      dendritic cell costimulation. sCTLA-4 KD Treg cells, in contrast with wild-type 
      Treg cells, failed to inhibit colitis induced by transfer of CD4(+)CD45RB(hi) 
      cells into NOD.SCID animals. Furthermore, diminished sCTLA-4 expression 
      accelerated the onset of autoimmune diabetes in transgenic mice. CONCLUSIONS: Our 
      results demonstrate that sCTLA-4 participates in immune regulation by 
      potentiating the function of Treg cells. The functional outcome of silencing this 
      splice variant in the NOD model provides an explanation for the association of 
      CTLA4 variation with autoimmunity. Lower sCTLA-4 expression from the 
      susceptibility allele may directly affect the suppressive capacity of Treg cells 
      and thereby modulate disease risk. Our unprecedented approach establishes the 
      feasibility of modeling splicing variations relevant to autoimmunity.
CI  - (c) 2011 by the American Diabetes Association.
FAU - Gerold, Kay D
AU  - Gerold KD
AD  - Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, 
      University of Wurzburg, Wurzburg, Germany.
FAU - Zheng, Peilin
AU  - Zheng P
FAU - Rainbow, Daniel B
AU  - Rainbow DB
FAU - Zernecke, Alma
AU  - Zernecke A
FAU - Wicker, Linda S
AU  - Wicker LS
FAU - Kissler, Stephan
AU  - Kissler S
LA  - eng
GR  - 079895/WT_/Wellcome Trust/United Kingdom
GR  - P01 AI039671/AI/NIAID NIH HHS/United States
GR  - U19 AI050864/AI/NIAID NIH HHS/United States
GR  - P01-AI-39671/AI/NIAID NIH HHS/United States
GR  - 091157/WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110520
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Antigens, CD)
RN  - 0 (CTLA-4 Antigen)
RN  - 0 (Ctla4 protein, mouse)
RN  - 0 (Protein Isoforms)
SB  - IM
MH  - Alternative Splicing
MH  - Animals
MH  - Antigens, CD/*genetics/*physiology
MH  - CTLA-4 Antigen
MH  - Diabetes Mellitus, Type 1/immunology/*prevention & control
MH  - Gene Knockdown Techniques
MH  - Mice
MH  - Mice, Inbred NOD
MH  - Mice, Transgenic
MH  - Protein Isoforms/genetics/physiology
MH  - T-Lymphocytes, Regulatory/immunology
PMC - PMC3121435
EDAT- 2011/05/24 06:00
MHDA- 2011/08/30 06:00
PMCR- 2012/07/01
CRDT- 2011/05/24 06:00
PHST- 2011/05/24 06:00 [entrez]
PHST- 2011/05/24 06:00 [pubmed]
PHST- 2011/08/30 06:00 [medline]
PHST- 2012/07/01 00:00 [pmc-release]
AID - db11-0130 [pii]
AID - 0130 [pii]
AID - 10.2337/db11-0130 [doi]
PST - ppublish
SO  - Diabetes. 2011 Jul;60(7):1955-63. doi: 10.2337/db11-0130. Epub 2011 May 20.