| CD46 engagement on human CD4+ T cells produces T regulatory type 1-like regulation of antimycobacterial T cell responses. | |
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MedLine Citation:
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PMID: 20921150 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Steven M Truscott; Getahun Abate; Jeffrey D Price; Claudia Kemper; John P Atkinson; Daniel F Hoft |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-10-04 |
Journal Detail:
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Title: Infection and immunity Volume: 78 ISSN: 1098-5522 ISO Abbreviation: Infect. Immun. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-11-16 Completed Date: 2010-12-15 Revised Date: 2011-07-28 |
Medline Journal Info:
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Nlm Unique ID: 0246127 Medline TA: Infect Immun Country: United States |
Other Details:
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Languages: eng Pagination: 5295-306 Citation Subset: IM |
Affiliation:
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Department of Internal Medicine, Division of Immunobiology, Saint Louis University, St. Louis, MO 63104, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antibodies, Monoclonal
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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:
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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:
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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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