TY - JOUR
T1 - Endocytic sequestration of the B cell antigen receptor and toll-like receptor 9 in anergic cells
AU - O'Neill, Shannon K.
AU - Veselits, Margaret L.
AU - Zhang, Miao
AU - Labno, Christine
AU - Cao, Yanxia
AU - Finnegan, Alison
AU - Uccellini, Melissa
AU - Alegre, Maria Luisa
AU - Cambier, John C.
AU - Clark, Marcus R.
PY - 2009/4/14
Y1 - 2009/4/14
N2 - 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.
AB - 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.
KW - Anergy
KW - endocytic trafficking
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U2 - 10.1073/pnas.0812922106
DO - 10.1073/pnas.0812922106
M3 - Article
C2 - 19332776
AN - SCOPUS:65549136622
SN - 0027-8424
VL - 106
SP - 6262
EP - 6267
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 15
ER -