TLR9 ligand sequestration by chemokine CXCL4 negatively affects central B cell tolerance
Publication date
2023-12-04
Authors
Çakan, Elif
Kioon, Marie Dominique Ah
Garcia-Carmona, Yolanda
Glauzy, Salomé
Oliver, David
Yamakawa, Natsuko
Loza, Andrea Vega
Du, Yong
Schickel, Jean Nicolas
Boeckers, Joshua M.
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Advisors
Supervisors
Document Type
Article
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cc_by_nc_sa
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.
Keywords
Immunology and Allergy, Immunology
Citation
Çakan, E, Kioon, M D A, Garcia-Carmona, Y, Glauzy, S, Oliver, D, Yamakawa, N, Loza, A V, Du, Y, Schickel, J N, Boeckers, J M, Yang, C, Baldo, A, Ivashkiv, L B, Young, R M, Staudt, L M, Moody, K L, Nündel, K, Marshak-Rothstein, A, van der Made, C I, Hoischen, A, Hayward, A, Rossato, M, Radstake, T R D J, Cunningham-Rundles, C, Ryu, C, Herzog, E L, Barrat, F J & Meffre, E 2023, 'TLR9 ligand sequestration by chemokine CXCL4 negatively affects central B cell tolerance', Journal of Experimental Medicine, vol. 220, no. 12, e20230944. https://doi.org/10.1084/jem.20230944