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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2022-10-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI156254 |
| _version_ | 1827768231235944448 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Hiromitsu Asashima |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-11T12:09:24Z |
| format | Article |
| id | doaj.art-0c9d8420a9fe4098b16d60ae27757205 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:09:24Z |
| publishDate | 2022-10-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-0c9d8420a9fe4098b16d60ae277572052023-11-07T16:19:26ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-10-0113220Impaired TIGIT expression on B cells drives circulating follicular helper T cell expansion in multiple sclerosisHiromitsu AsashimaPierre-Paul AxisaThi Hong Giang PhamErin E. LongbrakeWilliam E. RuffNikhil LeleInessa CohenKhadir RaddassiTomokazu S. SumidaDavid A. HaflerB 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.https://doi.org/10.1172/JCI156254AutoimmunityImmunology |
| spellingShingle | 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 Impaired TIGIT expression on B cells drives circulating follicular helper T cell expansion in multiple sclerosis The Journal of Clinical Investigation Autoimmunity Immunology |
| 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 | Autoimmunity Immunology |
| url | https://doi.org/10.1172/JCI156254 |
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