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Impaired TIGIT expression on B cells drives circulating follicular helper T cell expansion in multiple sclerosis

B cell depletion in patients with relapsing-remitting multiple sclerosis (RRMS) markedly prevents new MRI-detected lesions and disease activity, suggesting the hypothesis that altered B cell function leads to the activation of T cells driving disease pathogenesis. Here, we performed comprehensive an...

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Autores principales: Asashima, Hiromitsu, Axisa, Pierre-Paul, Pham, Thi Hong Giang, Longbrake, Erin E., Ruff, William E., Lele, Nikhil, Cohen, Inessa, Raddassi, Khadir, Sumida, Tomokazu S., Hafler, David A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9566906/
https://www.ncbi.nlm.nih.gov/pubmed/36250467
http://dx.doi.org/10.1172/JCI156254
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author Asashima, Hiromitsu
Axisa, Pierre-Paul
Pham, Thi Hong Giang
Longbrake, Erin E.
Ruff, William E.
Lele, Nikhil
Cohen, Inessa
Raddassi, Khadir
Sumida, Tomokazu S.
Hafler, David A.
author_facet Asashima, Hiromitsu
Axisa, Pierre-Paul
Pham, Thi Hong Giang
Longbrake, Erin E.
Ruff, William E.
Lele, Nikhil
Cohen, Inessa
Raddassi, Khadir
Sumida, Tomokazu S.
Hafler, David A.
author_sort Asashima, Hiromitsu
collection PubMed
description B cell depletion in patients with relapsing-remitting multiple sclerosis (RRMS) markedly prevents new MRI-detected lesions and disease activity, suggesting the hypothesis that altered B cell function leads to the activation of T cells driving disease pathogenesis. Here, we performed comprehensive analyses of CD40 ligand– (CD40L-) and IL-21–stimulated memory B cells from patients with MS and healthy age-matched controls, modeling the help of follicular helper T cells (Tfh cells), and found a differential gene expression signature in multiple B cell pathways. Most striking was the impaired TIGIT expression on MS-derived B cells mediated by dysregulation of the transcription factor TCF4. Activated circulating Tfh cells (cTfh cells) expressed CD155, the ligand of TIGIT, and TIGIT on B cells revealed their capacity to suppress the proliferation of IL-17–producing cTfh cells via the TIGIT/CD155 axis. Finally, CCR6(+) cTfh cells were significantly increased in patients with MS, and their frequency was inversely correlated with that of TIGIT(+) B cells. Together, these data suggest that the dysregulation of negative feedback loops between TIGIT(+) memory B cells and cTfh cells in MS drives the activated immune system in this disease.
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spelling pubmed-95669062022-10-18 Impaired TIGIT expression on B cells drives circulating follicular helper T cell expansion in multiple sclerosis Asashima, Hiromitsu Axisa, Pierre-Paul Pham, Thi Hong Giang Longbrake, Erin E. Ruff, William E. Lele, Nikhil Cohen, Inessa Raddassi, Khadir Sumida, Tomokazu S. Hafler, David A. J Clin Invest Research Article B cell depletion in patients with relapsing-remitting multiple sclerosis (RRMS) markedly prevents new MRI-detected lesions and disease activity, suggesting the hypothesis that altered B cell function leads to the activation of T cells driving disease pathogenesis. Here, we performed comprehensive analyses of CD40 ligand– (CD40L-) and IL-21–stimulated memory B cells from patients with MS and healthy age-matched controls, modeling the help of follicular helper T cells (Tfh cells), and found a differential gene expression signature in multiple B cell pathways. Most striking was the impaired TIGIT expression on MS-derived B cells mediated by dysregulation of the transcription factor TCF4. Activated circulating Tfh cells (cTfh cells) expressed CD155, the ligand of TIGIT, and TIGIT on B cells revealed their capacity to suppress the proliferation of IL-17–producing cTfh cells via the TIGIT/CD155 axis. Finally, CCR6(+) cTfh cells were significantly increased in patients with MS, and their frequency was inversely correlated with that of TIGIT(+) B cells. Together, these data suggest that the dysregulation of negative feedback loops between TIGIT(+) memory B cells and cTfh cells in MS drives the activated immune system in this disease. American Society for Clinical Investigation 2022-10-17 /pmc/articles/PMC9566906/ /pubmed/36250467 http://dx.doi.org/10.1172/JCI156254 Text en © 2022 Asashima et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Asashima, Hiromitsu
Axisa, Pierre-Paul
Pham, Thi Hong Giang
Longbrake, Erin E.
Ruff, William E.
Lele, Nikhil
Cohen, Inessa
Raddassi, Khadir
Sumida, Tomokazu S.
Hafler, David A.
Impaired TIGIT expression on B cells drives circulating follicular helper T cell expansion in multiple sclerosis
title Impaired TIGIT expression on B cells drives circulating follicular helper T cell expansion in multiple sclerosis
title_full Impaired TIGIT expression on B cells drives circulating follicular helper T cell expansion in multiple sclerosis
title_fullStr Impaired TIGIT expression on B cells drives circulating follicular helper T cell expansion in multiple sclerosis
title_full_unstemmed Impaired TIGIT expression on B cells drives circulating follicular helper T cell expansion in multiple sclerosis
title_short Impaired TIGIT expression on B cells drives circulating follicular helper T cell expansion in multiple sclerosis
title_sort impaired tigit expression on b cells drives circulating follicular helper t cell expansion in multiple sclerosis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9566906/
https://www.ncbi.nlm.nih.gov/pubmed/36250467
http://dx.doi.org/10.1172/JCI156254
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