4.7 Article

TLR9 ligand sequestration by chemokine CXCL4 negatively affects central B cell tolerance

Journal

JOURNAL OF EXPERIMENTAL MEDICINE
Volume 220, Issue 12, Pages -

Publisher

ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20230944

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TLR9 and CXCL4 play important roles in central B cell tolerance, with TLR9 regulating the removal of autoreactive clones and CXCL4 inhibiting TLR9 function by sequestering its ligands. The findings suggest that correcting defective TLR9 function may be a potential therapeutic strategy for restoring B cell tolerance in SSc patients.
TLR9 displays an important early tolerogenic function essential for central B cell tolerance, and CXCL4 inhibits TLR9 function in B cells from SSc patients by sequestering TLR9 ligands away from endosomal TLR9, leading to autoreactive B cell and autoantibody production. Central B cell tolerance is believed to be regulated by B cell receptor signaling induced by the recognition of self-antigens in immature B cells. Using humanized mice with defective MyD88, TLR7, or TLR9 expression, we demonstrate that TLR9/MYD88 are required for central B cell tolerance and the removal of developing autoreactive clones. We also show that CXCL4, a chemokine involved in systemic sclerosis (SSc), abrogates TLR9 function in B cells by sequestering TLR9 ligands away from the endosomal compartments where this receptor resides. The in vivo production of CXCL4 thereby impedes both TLR9 responses in B cells and the establishment of central B cell tolerance. We conclude that TLR9 plays an essential early tolerogenic function required for the establishment of central B cell tolerance and that correcting defective TLR9 function in B cells from SSc patients may represent a novel therapeutic strategy to restore B cell tolerance.

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