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 Hoischen

Anthony 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

10 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
Article number	e20230944
Journal	Journal of Experimental Medicine
Volume	220
Issue number	12
DOIs	https://doi.org/10.1084/jem.20230944
State	Published - 4 Dec 2023

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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

@article{6b88889175334c69aa4f192874721032,

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",

note = "Publisher Copyright: {\textcopyright} 2023 {\c C}akan et al.",

year = "2023",

month = dec,

day = "4",

doi = "10.1084/jem.20230944",

language = "English",

volume = "220",

journal = "Journal of Experimental Medicine",

issn = "0022-1007",

publisher = "Rockefeller University Press",

number = "12",

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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

TY - JOUR

T1 - TLR9 ligand sequestration by chemokine CXCL4 negatively affects central B cell tolerance

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.

UR - https://www.scopus.com/pages/publications/85172823611

U2 - 10.1084/jem.20230944

DO - 10.1084/jem.20230944

M3 - Article

C2 - 37773045

AN - SCOPUS:85172823611

SN - 0022-1007

VL - 220

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 12

M1 - e20230944

ER -

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

Abstract

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