Document Detail


Alloreactive CD8 T cells rescued from apoptosis during co-stimulation blockade by Toll-like receptor stimulation remain susceptible to Fas-induced cell death.
MedLine Citation:
PMID:  23190301     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Blockade of co-stimulatory signals to T cells is extremely effective for the induction of transplantation tolerance in immunologically naive rodents. However, infections and inflammation compromise the efficacy of co-stimulation blockade regimens for the induction of tolerance, thereby stimulating the rejection of allografts. Previous studies have shown that stimulation of innate immunity abrogates tolerance induction by preventing the deletion of alloreactive CD8(+) T cells that normally occurs during co-stimulation blockade. Although inflammation prevents the deletion of alloreactive T cells during co-stimulation blockade, it is not known if this resistance to cell death is the result of a mechanism intrinsic to the T cell. Here, we used syngeneic bone marrow chimeric mice that contain a trace population of T-cell receptor transgenic alloreactive CD8(+) T cells to investigate the early apoptotic signature and activation status of alloreactive T cells following exposure to inflammatory signals during co-stimulation blockade with an antibody specific for CD154. Our findings revealed that the presence of bacterial lipopolysaccharide during co-stimulation blockade enhanced the early activation of alloreactive CD8(+) T cells, as indicated by the up-regulation of CD25 and CD69, suppressed Fas ligand expression, and prevented apoptotic cell death. However, alloreactive CD8(+) T cells from lipopolysaccharide-treated mice remained sensitive to Fas-mediated apoptosis in vitro. These findings suggest that alloreactive T cells rescued from deletion during co-stimulation blockade by inflammation are still sensitive to pro-apoptotic signals and that stimulating these apoptotic pathways during co-stimulation blockade may augment the induction of tolerance.
Authors:
Bhavana Priyadharshini; Thomas B Thornley; Keith A Daniels; Amy Cuthbert; Raymond M Welsh; Dale L Greiner; Michael A Brehm
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Immunology     Volume:  138     ISSN:  1365-2567     ISO Abbreviation:  Immunology     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-13     Completed Date:  2013-04-26     Revised Date:  2014-04-01    
Medline Journal Info:
Nlm Unique ID:  0374672     Medline TA:  Immunology     Country:  England    
Other Details:
Languages:  eng     Pagination:  322-32     Citation Subset:  IM    
Copyright Information:
© 2012 Blackwell Publishing Ltd.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antibodies / pharmacology
Antigens, CD / genetics,  immunology
Antigens, CD95 / genetics,  immunology*
Antigens, Differentiation, T-Lymphocyte / genetics,  immunology
Apoptosis / drug effects*,  immunology
CD40 Ligand / antagonists & inhibitors,  genetics,  immunology
CD8-Positive T-Lymphocytes / drug effects*,  immunology
Fas Ligand Protein / genetics,  immunology*
Gene Expression Regulation / drug effects
Immune Tolerance / drug effects
Interleukin-2 Receptor alpha Subunit / genetics,  immunology
Lectins, C-Type / genetics,  immunology
Lipopolysaccharides / pharmacology
Lymphocyte Activation / drug effects
Male
Mice
Mice, Inbred C57BL
Signal Transduction / drug effects
Toll-Like Receptors / agonists,  genetics,  immunology*
Grant Support
ID/Acronym/Agency:
AI017672/AI/NIAID NIH HHS; AI042845/AI/NIAID NIH HHS; AI081675/AI/NIAID NIH HHS; AI083911/AI/NIAID NIH HHS; AI46629/AI/NIAID NIH HHS; R37 AI017672/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Antibodies; 0/Antigens, CD; 0/Antigens, CD95; 0/Antigens, Differentiation, T-Lymphocyte; 0/CD69 antigen; 0/Fas Ligand Protein; 0/Fas protein, mouse; 0/Interleukin-2 Receptor alpha Subunit; 0/Lectins, C-Type; 0/Lipopolysaccharides; 0/Toll-Like Receptors; 147205-72-9/CD40 Ligand
Comments/Corrections

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