Impaired TIGIT expression on B cells drives circulating follicular helper T cell expansion in multiple sclerosis
Hiromitsu Asashima, … , Tomokazu S. Sumida, David A. Hafler
Hiromitsu Asashima, … , Tomokazu S. Sumida, David A. Hafler
Published October 17, 2022
Citation Information: J Clin Invest. 2022;132(20):e156254. https://doi.org/10.1172/JCI156254.
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Research Article Autoimmunity Immunology

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

Abstract

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.

Authors

Hiromitsu Asashima, Pierre-Paul Axisa, Thi Hong Giang Pham, Erin E. Longbrake, William E. Ruff, Nikhil Lele, Inessa Cohen, Khadir Raddassi, Tomokazu S. Sumida, David A. Hafler

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Figure 5

The CD40/TCF4/TIGIT axis is dysregulated on MS-derived memory B cells.

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The CD40/TCF4/TIGIT axis is dysregulated on MS-derived memory B cells. (...
(A–C) CD20+CD27+ memory B cells were transfected with siRNAs targeting ID2 and ID3 (siID2/ID3) or with siCtrl (n = 4). (A) Representative flow data for TIGIT expression. (B) Proportion of TIGIT+ cells by flow cytometric analysis. (C) TIGIT, TCF4, ID2, and ID3 expression levels were measured relative to B2M by qPCR (FC versus the siRNA/siXBP1 condition). (D and E) Sorted CD20+CD27+ memory B cells from healthy donors (n = 12) and patients with MS (n = 12) were cultured with CD40L+IL-21 for 2 days, and ID2, ID3 (D), and TCF4 (E) expression levels were measured relative to B2M by qPCR. All data are presented as the mean ± SEM and were evaluated by 2-tailed, unpaired Student’s t test (B, D, and E).