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

Elif Çakan; Marie Dominique Ah Kioon; Yolanda Garcia-Carmona; Salomé Glauzy; David 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 L. 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

doi:10.1084/jem.20230944

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

Elif Çakan, Marie Dominique Ah Kioon, Yolanda Garcia-Carmona, Salomé Glauzy, David 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 L. Moody, Kerstin Nündel, Ann Marshak-Rothstein, Caspar I. van der Made, Alexander HoischenAnthony Hayward, Marzia Rossato, Timothy R.D.J. Radstake, Charlotte Cunningham-Rundles, Changwan Ryu, Erica L. Herzog, Franck J. Barrat, Eric Meffre

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English (US)
Article number	e20230944
Journal	Journal of Experimental Medicine
Volume	220
Issue number	12
DOIs	https://doi.org/10.1084/jem.20230944
State	Published - Dec 4 2023
Externally published	Yes

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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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., ... Meffre, E. (2023). TLR9 ligand sequestration by chemokine CXCL4 negatively affects central B cell tolerance. Journal of Experimental Medicine, 220(12), Article e20230944. https://doi.org/10.1084/jem.20230944

Çakan, E, Kioon, MDA, Garcia-Carmona, Y, Glauzy, S, Oliver, D, Yamakawa, N, Loza, AV, Du, Y, Schickel, JN, Boeckers, JM, Yang, C, Baldo, A, Ivashkiv, LB, Young, RM, Staudt, LM, Moody, KL, Nündel, K, Marshak-Rothstein, A, van der Made, CI, Hoischen, A, Hayward, A, Rossato, M, Radstake, TRDJ, Cunningham-Rundles, C, Ryu, C, Herzog, EL, Barrat, FJ & 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

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title = "TLR9 ligand sequestration by chemokine CXCL4 negatively affects central B cell tolerance",

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.",

author = "Elif {\c C}akan and Kioon, {Marie Dominique Ah} and Yolanda Garcia-Carmona and Salom{\'e} Glauzy and David Oliver and Natsuko Yamakawa and Loza, {Andrea Vega} and Yong Du and Schickel, {Jean Nicolas} and Boeckers, {Joshua M.} and Chao Yang and Alessia Baldo and Ivashkiv, {Lionel B.} and Young, {Ryan M.} and Staudt, {Louis M.} and Moody, {Krishna L.} and Kerstin N{\"u}ndel and Ann Marshak-Rothstein and {van der Made}, {Caspar I.} and Alexander Hoischen and Anthony Hayward and Marzia Rossato and Radstake, {Timothy R.D.J.} and Charlotte Cunningham-Rundles and Changwan Ryu and Herzog, {Erica L.} and Barrat, {Franck J.} and Eric Meffre",

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doi = "10.1084/jem.20230944",

language = "English (US)",

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AU - Çakan, Elif

AU - Kioon, Marie Dominique Ah

AU - Garcia-Carmona, Yolanda

AU - Glauzy, Salomé

AU - Oliver, David

AU - Yamakawa, Natsuko

AU - Loza, Andrea Vega

AU - Du, Yong

AU - Schickel, Jean Nicolas

AU - Boeckers, Joshua M.

AU - Yang, Chao

AU - Baldo, Alessia

AU - Ivashkiv, Lionel B.

AU - Young, Ryan M.

AU - Staudt, Louis M.

AU - Moody, Krishna L.

AU - Nündel, Kerstin

AU - Marshak-Rothstein, Ann

AU - van der Made, Caspar I.

AU - Hoischen, Alexander

AU - Hayward, Anthony

AU - Rossato, Marzia

AU - Radstake, Timothy R.D.J.

AU - Cunningham-Rundles, Charlotte

AU - Ryu, Changwan

AU - Herzog, Erica L.

AU - Barrat, Franck J.

AU - Meffre, Eric

PY - 2023/12/4

Y1 - 2023/12/4

N2 - 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.

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

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