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 6

TIGIT+ B cells suppress the proliferation of CCR6+ Tfh cells.

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TIGIT+ B cells suppress the proliferation of CCR6+ Tfh cells. (A–C) Sort...
(A–C) Sorted CD4+CD45RA–CXCR5+ Tfh cells and CD4+CD45RA–CXCR5– non-Tfh cells were stimulated with anti-CD3/anti-CD28 antibodies (each 1 μg/mL) for 3 days. Representative flow data for CD155 expression (A, left) and the proportion of CD155+ cells (A, right) (n = 10) are shown. (B) PVR mRNA expression was measured relative to B2M by qPCR (n = 7). (C) Proportion of CD112+ cells (n = 10). (D) Experimental workflow for coculture assays with sorted CD20+CD27+ memory B cells and CD4+CD45RA–CXCR5+ Tfh cells. (E) Representative flow data for Tfh cell proliferation. (F) Proportion of proliferated CellTrace Violet+ (CTV+) cells. (G) IL-17 and IFN-γ expression in the supernatants of coculture assays was evaluated by ELISA. (H) Correlation between CD4+CD45RA–CXCR5+CCR6+ Tfh cells (percentage of CD4+CD45RA–CXCR5+ Tfh cells) and TIGIT+ cells (percentage of CD20+CD27+ memory B cells). Data for healthy donors are indicated by blue dots (n = 15) and by red dots for patients with MS (n = 16). Linear regression is shown with a 95% CI (pink area). (I) Proportion of CCR6+ Tfh cells between healthy donors (n = 18) and patients with MS (n = 17). Data are presented as the mean ± SEM and were evaluated by 2-tailed, unpaired Student’s t test (A–C and I) or Wilcoxon matched-pairs, signed-rank test (F and G).