TLR9 ligand sequestration by chemokine CXCL4 negatively affects central B cell tolerance
Elif Çakan, Marie Dominique Ah Kioon, Yolanda García-Carmona, Salomé Glauzy, David J. Oliver, Natsuko Yamakawa, Andrea Vega Loza, Yong Du, Jean-Nicolas Schickel, Joshua M. Boeckers, Chao Yang, Alessia Baldo, Lionel B. Ivashkiv, Ryan M. Young, Louis M. Staudt, Krishna Moody, Kerstin Nündel, Ann Marshak‐Rothstein, Caspar I. van der Made, Alexander Hoischen, Anthony Hayward, Marzia Rossato, Timothy R. D. J. Radstake, Charlotte Cunningham‐Rundles, Changwan Ryu, Erica L. Herzog, Franck J. Barrat, Eric Meffre
Abstract
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.