Type I IFN receptor and the B cell antigen receptor regulate TLR7 responses via distinct molecular mechanisms

Jayakumar S Poovassery; Gail A Bishop

doi:10.4049/jimmunol.1200624

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Type I IFN receptor and the B cell antigen receptor regulate TLR7 responses via distinct molecular mechanisms

Journal article

Open access

Peer reviewed

Type I IFN receptor and the B cell antigen receptor regulate TLR7 responses via distinct molecular mechanisms

Jayakumar S Poovassery and Gail A Bishop

The Journal of immunology (1950), Vol.189(4), pp.1757-1764

08/15/2012

DOI: 10.4049/jimmunol.1200624

PMID: 22786773

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Abstract

Toll-like receptor 7 (TLR7) signals to B cells are critically involved in the innate immune response to microbes, as well as pathogenesis of autoimmune diseases, but the molecular mechanisms that normally regulate these responses are incompletely understood. We previously reported that repeated stimulation through TLR7 induces a state of hyporesponsiveness (TLR tolerance) in both human and mouse B cells, characterized by marked inhibition of particular signaling pathways. BCR signals prevent and overcome TLR7 tolerance. Because optimal responses to TLR7 in B cells require type I IFN, we investigated whether BCR-mediated effects on TLR7 tolerance are mediated by type I IFN receptor (IFNAR) signals. Surprisingly, although BCR-mediated reversal of TLR7 tolerance was IFNAR independent, IFNAR signals alone also blocked TLR7 tolerance, despite enhancing TLR7 expression. Both BCR and IFNAR signals restored the phosphorylation of the transcriptional regulator c-Jun, but only BCR signals blocked the tolerance-mediated inhibition of JNK. Both BCR and IFNAR-mediated regulation was dependent on activation of the PI3K/Akt/mammalian target of rapamycin signaling pathway, indicating a central role for this axis in integrating TLR7, BCR, and IFNAR signals in B cells. These new findings reveal distinct and overlapping signaling mechanisms used by BCR and IFNAR in the regulation of TLR7 tolerance and activation.

Toll-Like Receptor 7 - metabolism

Humans

Mice, Inbred C57BL

Receptors, Antigen, B-Cell - metabolism

Blotting, Western

Receptors, Antigen, B-Cell - immunology

Immunity, Innate - immunology

Signal Transduction - immunology

Lymphocyte Activation - immunology

Animals

B-Lymphocytes - immunology

Receptor, Interferon alpha-beta - immunology

Immune Tolerance - immunology

Toll-Like Receptor 7 - immunology

Mice

Receptor, Interferon alpha-beta - metabolism

Details

Title: Subtitle: Type I IFN receptor and the B cell antigen receptor regulate TLR7 responses via distinct molecular mechanisms
Creators: Jayakumar S Poovassery - Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA
Gail A Bishop
Resource Type: Journal article
Publication Details: The Journal of immunology (1950), Vol.189(4), pp.1757-1764
Publisher: United States
DOI: 10.4049/jimmunol.1200624
PMID: 22786773
ISSN: 0022-1767
eISSN: 1550-6606
Language: English
Date published: 08/15/2012
Academic Unit: Microbiology and Immunology; President
Record Identifier: 9984002396002771

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