c-Met enforces proinflammatory and migratory features of human activated CD4+ T cells

Benkhoucha, Mahdia; Tran, Ngoc Lan; Bréville, Gautier; Senoner, Isis; Jandus, Camilla; Lalive, Patrice H.

doi:10.1038/s41423-021-00721-9

Cited by 4 publications

(4 citation statements)

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“…The results showed an increase of CD4 + cMet + population in the blood of MS patients (Fig. 6B) as previously described [25]. We next analyzed in MS patients the expression of Itgα4 on CD4 + c-Met − and CD4 + c-Met + T cells by flow cytometry and we found an increase expression of Itgα4 on CD4 + c-Met + T cells, compared to their c-Met − counterparts (Fig.…”

Section: Increased Endogenous Cd4 + C-met + Itgα4 + T Cells In Ms Pat...supporting

confidence: 86%

“…In addition, we uncovered the presence of human c-Met-expressing CD4 + T cells upon TCR triggering. CD4 + c-Met + T cells revealed an enhanced pro-inflammatory phenotype skewed towards a Th17 and Th17.1 polarization, and higher levels of Itgα4 compared to CD4 + c-Met − T cells [25]. Nevertheless, the expression of c-Met on CD4 + T cells-as well as its possible function-in model of neuroinflammation is unknown.…”

Section: Discussionmentioning

confidence: 98%

“…In addition, we recently identified the presence of human c-Met-expressing CD4 + T cells upon T cell receptor (TCR) triggering. Phenotypic and functional analyses of CD4 + c-Met + T cells revealed an enhanced pro-inflammatory phenotype skewed towards a Th17 and Th17.1 polarization, with increased production of IL-17 alone or both IL-17/IFNγ (double positive) and higher levels of Itgα4 compared to CD4 + c-Met − T cells [25].…”

Section: Introductionmentioning

confidence: 98%

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CD4+c-Met+Itgα4+ T cell subset promotes murine neuroinflammation

Benkhoucha

Tran

Bréville

et al. 2022

J Neuroinflammation

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Objective c-Met, a tyrosine kinase receptor, is the unique receptor for hepatocyte growth factor (HGF). The HGF/c-Met axis is reported to modulate cell migration, maturation, cytokine production, and antigen presentation. Here, we report that CD4+c-Met+ T cells are detected at increased levels in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS). Methods c-Met expression by CD4+ T cells was analyzed mostly by flow cytometry and by immunohistochemistry from mice and human PBMCs. The in vivo role of CD4+c-Met+ T cells was assessed in EAE. Results CD4+c-Met+ T cells found in the CNS during EAE peak disease are characterized by a pro-inflammatory phenotype skewed towards a Th1 and Th17 polarization, with enhanced adhesion and transmigration capacities correlating with increased expression of integrin α4 (Itgα4). The adoptive transfer of Itgα4-expressing CD4+Vα3.2+c-Met+ T cells induces increased disease severity compared to CD4+Vα3.2+c-Met− T cells. Finally, CD4+c-Met+ T cells are detected in the brain of MS patients, as well as in the blood with a higher level of Itgα4. These results highlight c-Met as an immune marker of highly pathogenic pro-inflammatory and pro-migratory CD4+ T lymphocytes associated with neuroinflammation.

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Section: Increased Endogenous Cd4 + C-met + Itgα4 + T Cells In Ms Pat...supporting

confidence: 86%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 98%

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CD4+c-Met+Itgα4+ T cell subset promotes murine neuroinflammation

Benkhoucha

Tran

Bréville

et al. 2022

J Neuroinflammation

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“…The receptor tyrosine kinase c-Met plays a pivotal role in embryonic development and tissue regeneration, and influences critical cellular processes such as cell survival, proliferation, migration, and angiogenesis [36] The HGF/c-Met axis actively participates in the regulation of numerous inflammatory-mediated diseases by engaging a diverse array of cell types [37]. Extensive research has established the HGF/c-Met signaling pathway as a promising target for personalized cancer treatment, especially when expressed on tumor cells [38,39].…”

Section: Discussionmentioning

confidence: 99%

c-Met+ Cytotoxic T Lymphocytes Exhibit Enhanced Cytotoxicity in Mice and Humans In Vitro Tumor Models

Benkhoucha,

Tran,

Senoner

et al. 2023

Biomedicines

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CD8+ cytotoxic T lymphocytes (CTLs) play a crucial role in anti-tumor immunity. In a previous study, we identified a subset of murine effector CTLs expressing the hepatocyte growth factor (HGF) receptor, c-Met (c-Met+ CTLs), that are endowed with enhanced cytolytic capacity. HGF directly inhibited the cytolytic function of c-Met+ CTLs, both in 2D in vitro assays and in vivo, leading to reduced T cell responses against metastatic melanoma. To further investigate the role of c-Met+ CTLs in a three-dimensional (3D) setting, we studied their function within B16 melanoma spheroids and examined the impact of cell–cell contact on the modulation of inhibitory checkpoint molecules’ expression, such as KLRG1, PD-1, and CTLA-4. Additionally, we evaluated the cytolytic capacity of human CTL clones expressing c-Met (c-Met+) and compared it to c-Met− CTL clones. Our results indicated that, similar to their murine counterparts, c-Met+ human CTL clones exhibited increased cytolytic activity compared to c-Met− CTL clones, and this enhanced function was negatively regulated by the presence of HGF. Taken together, our findings highlight the potential of targeting the HGF/c-Met pathway to modulate CTL-mediated anti-tumor immunity. This research holds promise for developing strategies to enhance the effectiveness of CTL-based immunotherapies against cancer.

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