Pro-inflammatory T helper 17 directly harms oligodendrocytes in neuroinflammation

Larochelle, Catherine; Wasser, Beatrice; Jamann, Hélène; Löffel, Julian T.; Cui, Qiao‐Ling; Tastet, Olivier; Schillner, Miriam; Luchtman, Dirk; Birkenstock, Jérôme; Stroh, Albrecht; Antel, Jack; Bittner, Stefan; Zipp, Frauke

doi:10.1073/pnas.2025813118

Cited by 38 publications

(34 citation statements)

References 86 publications

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“…In addition, we established that Th17-polarized cells induce both OL process damage and OL cell death in mouse and human systems. While we identified the contribution of CD29-triggered glutamate secretion by Th17-polarized cells to OL process injury and myelination impairment, glutamate did not induce death of human OLs in primary culture ( 17 ). Human OLs are highly resistant to induction of programmed cell death upon exposure to stressors such as high doses of tumor necrosis factor alpha (TNFα) or glutamate, or deprivation of glucose ( 17 – 20 ).…”

Section: Introductionmentioning

confidence: 95%

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Contact-Dependent Granzyme B-Mediated Cytotoxicity of Th17-Polarized Cells Toward Human Oligodendrocytes

et al. 2022

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Multiple sclerosis (MS) is characterized by the loss of myelin and of myelin-producing oligodendrocytes (OLs) in the central nervous system (CNS). Pro-inflammatory CD4+ Th17 cells are considered pathogenic in MS and are harmful to OLs. We investigated the mechanisms driving human CD4+ T cell-mediated OL cell death. Using fluorescent and brightfield in vitro live imaging, we found that compared to Th2-polarized cells, Th17-polarized cells show greater interactions with primary human OLs and human oligodendrocytic cell line MO3.13, displaying longer duration of contact, lower mean speed, and higher rate of vesicle-like structure formation at the sites of contact. Using single-cell RNA sequencing, we assessed the transcriptomic profile of primary human OLs and Th17-polarized cells in direct contact or separated by an insert. We showed that upon close interaction, OLs upregulate the expression of mRNA coding for chemokines and antioxidant/anti-apoptotic molecules, while Th17-polarized cells upregulate the expression of mRNA coding for chemokines and pro-inflammatory cytokines such as IL-17A, IFN-γ, and granzyme B. We found that secretion of CCL3, CXCL10, IFN-γ, TNFα, and granzyme B is induced upon direct contact in cocultures of human Th17-polarized cells with human OLs. In addition, we validated by flow cytometry and immunofluorescence that granzyme B levels are upregulated in Th17-polarized compared to Th2-polarized cells and are even higher in Th17-polarized cells upon direct contact with OLs or MO3.13 cells compared to Th17-polarized cells separated from OLs by an insert. Moreover, granzyme B is detected in OLs and MO3.13 cells following direct contact with Th17-polarized cells, suggesting the release of granzyme B from Th17-polarized cells into OLs/MO3.13 cells. To confirm granzyme B–mediated cytotoxicity toward OLs, we showed that recombinant human granzyme B can induce OLs and MO3.13 cell death. Furthermore, pretreatment of Th17-polarized cells with a reversible granzyme B blocker (Ac-IEPD-CHO) or a natural granzyme B blocker (serpina3N) improved survival of MO3.13 cells upon coculture with Th17 cells. In conclusion, we showed that human Th17-polarized cells form biologically significant contacts with human OLs and exert direct toxicity by releasing granzyme B.

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Section: Introductionmentioning

confidence: 95%

“…We have recently reported that Th17 cells can form prolonged contact with OLs in vivo in EAE ( 17 ). In addition, we established that Th17-polarized cells induce both OL process damage and OL cell death in mouse and human systems.…”

Section: Introductionmentioning

confidence: 99%

Contact-Dependent Granzyme B-Mediated Cytotoxicity of Th17-Polarized Cells Toward Human Oligodendrocytes

et al. 2022

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“…Visweswaran et al observed a sustained decrease in the frequency of the Th17 subset at both 24 and 36 months, but with no change in absolute Th17 cell numbers [ 36 ]. Of note, Th17 is thought to directly participate in MS-associated neuroinflammation and damage oligodendrocytes [ 100 ]. Numerous studies report that CD4+ T cell populations do not return to baseline 2 years post-aHSCT, with altered CD4+ /CD8+ T cell ratios, therefore, persisting in the long term [ 47 , 62 , 96 , 97 , 101 ].…”

Section: Immune Reconstitution Following Ahsctmentioning

confidence: 99%

The current standing of autologous haematopoietic stem cell transplantation for the treatment of multiple sclerosis

et al. 2022

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Autologous haematopoietic stem cell transplantation (aHSCT) is gaining traction as a valuable treatment option for patients affected by severe multiple sclerosis (MS), particularly the relapsing–remitting form. We describe the current literature in terms of clinical trials, observational and retrospective studies, as well as immune reconstitution following transplantation, with a focus on the conditioning regimens used for transplantation. The evidence base predominantly consists of non-randomised, uncontrolled clinical trials or data from retrospective or observational cohorts, i.e. very few randomised or controlled trials. Most often, intermediate-intensity conditioning regimens are used, with promising results from both myeloablative and lymphoablative strategies, as well as from regimens that are low and high intensity. Efficacy of transplantation, which is likely secondary to immune reconstitution and restored immune tolerance, is, therefore, not clearly dependent on the intensity of the conditioning regimen. However, the conditioning regimen may well influence the immune response to transplantation. Heterogeneity of conditioning regimens among studies hinders synthesis of the articles assessing post-aHSCT immune system changes. Factors associated with better outcomes were lower Kurtzke Expanded Disability Status Scale, relapsing–remitting MS, younger age, and shorter disease duration at baseline, which supports the guidance for patient selection proposed by the European Society for Blood and Marrow Transplantation. Interestingly, promising outcomes were described for patients with secondary progressive MS by some studies, which may be worth taking into account when considering treatment options for patients with active, progressive disease. Of note, a significant proportion of patients develop autoimmune disease following transplantation, with alemtuzumab-containing regimens associated with the highest incidence.

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“…These measurements are dependent on the total time an object is being tracked, the time interval between images and the accuracy of the tracking analysis. Many studies have used velocity and angle to quantify T cell migration patterns 1,8,9,19,69‐71 . These measurements were important to elucidate the behavior patterns observed in the initial T cell priming and effector stages (Figure 1A).…”

Section: Approaches For Quantifying Immune Cell Behaviormentioning

confidence: 99%

“…Many studies have used velocity and angle to quantify T cell migration patterns. 1,8,9,19,[69][70][71] These measurements were important to elucidate the behavior patterns observed in the initial T cell priming and effector stages (Figure 1A). But to extract additional behavior patterns that are more subtle may require the integration of different measures.…”

Section: Approache S For Quantif Ying Immune Cell B Ehaviormentioning

confidence: 99%

Moving beyond velocity: Opportunities and challenges to quantify immune cell behavior*

Schienstock

Mueller

2021

Immunological Reviews

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The analysis of cellular behavior using intravital multi‐photon microscopy has contributed substantially to our understanding of the priming and effector phases of immune responses. Yet, many questions remain unanswered and unexplored. Though advancements in intravital imaging techniques and animal models continue to drive new discoveries, continued improvements in analysis methods are needed to extract detailed information about cellular behavior. Focusing on dendritic cell (DC) and T cell interactions as an exemplar, here we discuss key limitations for intravital imaging studies and review and explore alternative approaches to quantify immune cell behavior. We touch upon current developments in deep learning models, as well as established methods from unrelated fields such as ecology to detect and track objects over time. As developments in open‐source software make it possible to process and interactively view larger datasets, the challenge for the field will be to determine how best to combine intravital imaging with multi‐parameter imaging of larger tissue regions to discover new facets of leukocyte dynamics and how these contribute to immune responses.

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Pro-inflammatory T helper 17 directly harms oligodendrocytes in neuroinflammation

Cited by 38 publications

References 86 publications

Contact-Dependent Granzyme B-Mediated Cytotoxicity of Th17-Polarized Cells Toward Human Oligodendrocytes

Contact-Dependent Granzyme B-Mediated Cytotoxicity of Th17-Polarized Cells Toward Human Oligodendrocytes

The current standing of autologous haematopoietic stem cell transplantation for the treatment of multiple sclerosis

Moving beyond velocity: Opportunities and challenges to quantify immune cell behavior*

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