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

• Published in: The Journal of experimental medicine 2023-12, Vol.220 (12)
• Main Authors: Çakan, Elif, Ah Kioon, Marie Dominique, Garcia-Carmona, Yolanda, Glauzy, Salomé, Oliver, David, Yamakawa, Natsuko, Vega Loza, Andrea, Du, Yong, Schickel, Jean-Nicolas, Boeckers, Joshua M, Yang, Chao, Baldo, Alessia, Ivashkiv, Lionel B, Young, Ryan M, Staudt, Louis M, Moody, Krishna L, Nündel, Kerstin, Marshak-Rothstein, Ann, van der Made, Caspar I, Hoischen, Alexander, Hayward, Anthony, Rossato, Marzia, Radstake, Timothy R D J, Cunningham-Rundles, Charlotte, Ryu, Changwan, Herzog, Erica L, Barrat, Franck J, Meffre, Eric
• Format: Article
• Language: English
• Subjects: Animals; Autoimmunity; B-Lymphocytes; Humans; Ligands; Mice; Myeloid Differentiation Factor 88 - metabolism; Platelet Factor 4 - metabolism; Scleroderma, Systemic - metabolism; Toll-Like Receptor 7; Toll-Like Receptor 9 - metabolism
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20230944

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.