Document Detail


CD46 engagement on human CD4+ T cells produces T regulatory type 1-like regulation of antimycobacterial T cell responses.
MedLine Citation:
PMID:  20921150     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Understanding the regulation of human immune responses is critical for vaccine development and treating infectious diseases. We have previously shown that simultaneous engagement of the T cell receptor (TCR) and complement regulator CD46 on human CD4(+) T cells in the presence of interleukin-2 (IL-2) induces potent secretion of the immunomodulatory cytokine IL-10. These T cells mediate IL-10-dependent suppression of bystander CD4(+) T cells activated in vitro with anti-CD3 and anti-CD28 costimulation, reflecting a T regulatory type 1 (Tr1)-like phenotype. However, CD46-mediated negative regulation of pathogen-specific T cells has not been described. Therefore, we studied the ability of CD46-activated human CD4(+) T cells to suppress T cell responses to Mycobacterium bovis BCG, the live vaccine that provides infants protection against the major human pathogen Mycobacterium tuberculosis. Our results demonstrate that soluble factors secreted by CD46-activated human CD4(+) T cells suppress mycobacterium-specific CD4(+), CD8(+), and γ(9)δ(2) TCR(+) T cells. Dendritic cell functions were not downregulated in our experiments, indicating that CD46-triggered factors directly suppress pathogen-specific T cells. Interestingly, IL-10 appeared to play a less pronounced role in our system, especially in the suppression of γ(9)δ(2) TCR(+) T cells, suggesting the presence of additional undiscovered soluble immunoregulatory factors. Blocking endogenous CD46 signaling 3 days after mycobacterial infection enhanced BCG-specific T cell responses in a subset of volunteers. Taken together, these results indicate that CD46-dependent negative regulatory mechanisms can impair T cell responses vital for immune defense against mycobacteria. Therefore, modulating CD46-induced immune regulation could be integral to the development of improved tuberculosis therapeutics or vaccines.
Authors:
Steven M Truscott; Getahun Abate; Jeffrey D Price; Claudia Kemper; John P Atkinson; Daniel F Hoft
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-10-04
Journal Detail:
Title:  Infection and immunity     Volume:  78     ISSN:  1098-5522     ISO Abbreviation:  Infect. Immun.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-11-16     Completed Date:  2010-12-15     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  0246127     Medline TA:  Infect Immun     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5295-306     Citation Subset:  IM    
Affiliation:
Department of Internal Medicine, Division of Immunobiology, Saint Louis University, St. Louis, MO 63104, USA.
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MeSH Terms
Descriptor/Qualifier:
Antibodies, Monoclonal / immunology
Antigens, CD46 / immunology*
BCG Vaccine / immunology
CD4-Positive T-Lymphocytes / immunology*
Cells, Cultured
Flow Cytometry
Granulocyte-Macrophage Colony-Stimulating Factor / immunology
Humans
Hybridomas / immunology
Interleukin-10 / immunology
Interleukin-2 Receptor alpha Subunit / immunology
Lymphocyte Activation / immunology*
T-Lymphocytes, Regulatory / immunology*
Grant Support
ID/Acronym/Agency:
N01-AI-25464/AI/NIAID NIH HHS; P30 AR48335/AR/NIAMS NIH HHS; R01 AI037618/AI/NIAID NIH HHS; R01 AI48391/AI/NIAID NIH HHS; U19 AI070489/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Antigens, CD46; 0/BCG Vaccine; 0/Interleukin-2 Receptor alpha Subunit; 130068-27-8/Interleukin-10; 83869-56-1/Granulocyte-Macrophage Colony-Stimulating Factor
Comments/Corrections

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