Endocytic sequestration of the B cell antigen receptor and toll-like receptor 9 in anergic cells

In autoimmune prone murine strains, sequential engagement of the B cell antigen receptor (BCR) on the cell surface and toll-like receptors (TLRs) in late endosomes is necessary and sufficient for secretion of autoantibodies. However, ubiquitous nucleoprotein self-antigens fail to elicit productive T...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2009-04, Vol.106 (15), p.6262-6267
Main Authors: O'Neill, Shannon K, Veselits, Margaret L, Zhang, Miao, Labno, Christine, Cao, Yanxia, Finnegan, Alison, Uccellini, Melissa, Alegre, Maria-Luisa, Cambier, John C, Clark, Marcus R
Format: Article
Language:English
Subjects:
Animals
Antibodies
Antibodies, Antinuclear - genetics
Antibodies, Antinuclear - immunology
Antibodies, Antinuclear - metabolism
Antibodies, Antiphospholipid - genetics
Antibodies, Antiphospholipid - immunology
Antibodies, Antiphospholipid - metabolism
Antigens
Antigens, Ly - genetics
Antigens, Ly - immunology
Antigens, Ly - metabolism
B lymphocytes
B-Lymphocytes - immunology
Biological Sciences
Cells
Clonal Anergy - immunology
Endocytosis
Endocytosis - immunology
Endosomes
Enzyme Activation
Internalization
JNK Mitogen-Activated Protein Kinases - genetics
JNK Mitogen-Activated Protein Kinases - metabolism
Ligands
Mice
Mice, Inbred C57BL
Microscopy
Molecules
Protein Transport
Receptors
Receptors, Antigen, B-Cell - immunology
Spleen - immunology
T cell receptors
T lymphocytes
Time Factors
Toll like receptors
Toll-Like Receptor 9 - immunology
Ubiquitination
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Summary:In autoimmune prone murine strains, sequential engagement of the B cell antigen receptor (BCR) on the cell surface and toll-like receptors (TLRs) in late endosomes is necessary and sufficient for secretion of autoantibodies. However, ubiquitous nucleoprotein self-antigens fail to elicit productive TLR activation, and break self-tolerance in anergic DNA-reactive B cells. The mechanisms limiting TLR activation in these cells are largely unknown. Here, we demonstrate that in anergic 3H9/Vκ8 and Ars/A1 B cells the normal endocytic transit of both the ligated BCR and TLR9 into late endosomes is abrogated. The BCR and TLR9 arrest together just outside late endosomes, indicating that they enter this compartment along a single, regulated endocytic route. Access to late endosomes could be restored by reversing anergy through several methods, including conferring genetic susceptibility to autoimmunity, complementing proximal BCR signaling or by preventing BCR binding to self-antigen. Downstream of the BCR, JNK, which is activated in naive but not anergic B cells, regulated entry into late endosomes. Restoration of BCR and TLR9 endocytic trafficking rescued TLR9 activation by BCR-captured ligands. These results indicate that B cell anergy is reinforced by the exclusion of both TLRs and their BCR captured ligands from subcellular environments necessary for TLR activation.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0812922106