Impaired TIGIT expression on B cells drives circulating follicular helper T cell expansion in multiple sclerosis
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
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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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 1

TIGIT is downregulated on memory B cells in MS.

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TIGIT is downregulated on memory B cells in MS. (A–C) Sorted CD20+CD27+ ...
(A–C) Sorted CD20+CD27+ memory B cells from patients with MS (n = 8) and healthy donors (HD) (n = 9) were cultured with CD40L and IL-21 for 2 days, and RNA-Seq was performed. (A) Heatmap of DEGs (|log2 FC| >0.5, FDR < 0.1) in patients with MS and healthy donors. (B) Volcano plot depicting DEGs in memory B cells. Red dots represent significantly upregulated genes in MS-derived memory B cells, and blue dots represent significantly downregulated genes. Genes whose location is categorized as “plasma membrane” by IPA software are labeled. (C) IPA was performed to identify signatures related to altered molecular and cellular functions. Functions whose –log (Benjamini-Hochberg [B-H] P value) values were greater than 1.8 are shown. (D–F) Sorted CD20+CD27+ memory B cells from patients with MS and healthy donors (n = 12 each) were cultured with CD40L and IL-21 for 2 days. Gene expression was measured relative to B2M by qPCR (D and E). Representative flow data for TIGIT expression (F, left) and proportion of TIGIT+ cells (F, right). mB, memory B cells. Data are presented as the mean ± SEM and were evaluated by 2-tailed, unpaired Student’s t test (D–F). FSC-W, forward scatter width.