Biology subjects

Boulet, S.

Publications and source records attributed to Boulet, S..

8 recordsLinked to original sources

bioRxiv2026

The Notch signaling pathway is a master regulator of CD8+ T cell exhaustion and differentiation during chronic infection

During chronic infection, the persistence of antigen and inflammation leads to the differentiation of CD8+ T cells into an exhausted state characterised by expression of inhibitory receptors (IRs) and the progressive loss of T cell functions. Among the different subsets of exhausted CD8+ T (Tex) cells, Tex progenitors expressing SLAMF6 and the transcription factor TCF-1 (TCF-1+) give rise to Tex effector-like cells expressing CX3CR1 and Tex terminal cells expressing CD101. PD-1/PD-L1 blockade acts on TCF-1+ Tex progenitor cells and promotes their differentiation into Tex effector-like cells. The molecular events controlling CD8+ Tex cell differentiation are still poorly defined. As Notch signaling may be sustained during chronic infection by persistent TCR stimulation and inflammation, we tested whether Notch signaling influences CD8+ T cell exhaustion. Using mice lacking (N1N2{triangleup}/{triangleup}) or not (N1N2fl/fl) Notch1/2 expression only in mature CD8+ T cells, we showed that the absence of Notch signal causes severe CD8+ T cell exhaustion during chronic LCMV infection. N1N2{triangleup}/{triangleup} Tex cells express higher levels of IRs and are less functional when compared to their wild-typee counterpart. In the absence of N1N2 receptors, Tex progenitor and Tex terminal cells accumulate and Tex cells cannot be reinvigorated by PD-1/PD-L1 blockade. We further demonstrated that Notch signaling is essential to promote the differentiation of Tex progenitors into Tex effector-like cells. Moreover, Notch signals, provided by stromal cells expressing the ligands Delta-like 1 and 4, are necessary during all stages of the infection to prevent severe exhaustion. Single-nucleus RNA and ATAC multiome profiling identifies Notch signaling as a critical role on effector transcriptional programming in exhausted CD8 T cells. Loss of Notch signaling impairs transcriptional program associated with migration and perception of CD4+ T cell help. Together, these alterations drive the differentiation of Tex progenitor cells toward a terminally exhausted Tex fate.

immunology↗

bioRxiv2024

The orphan nuclear receptor NR4A3 is dispensable for resident memory CD8+ T cell generation

Different memory CD8+ T cell subsets are generated following acute responses: central, effector and resident (Trm). CD8+ Trm cells established residency at the sites of infection and provide an efficient and rapid frontline defense against re-infection. The NR4A family members (NR4A1, NR4A2 and NR4A3) of orphan nuclear receptor are transiently expressed following TCR signaling and NR4As were shown to influence CD8+ T cell response. Interestingly, Nr4a1, Nr4a2 and Nr4a3 have been reported to be transcribed by CD8+ Trm cells. In absence of NR4A1, less CD8+ Trm cells are present in the liver, lungs, small intestine intra-epithelial lymphocytes (IELs) and Peyers patches. NR4A2 was shown to play a role in the generation of small intestine IEL CD8+ Trm cells. However, evidence is still lacking for the contribution of NR4A3 during CD8+ Tm cell differentiation. In this study, we evaluated the role of NR4A3 in the differentiation and maintenance of CD8+ Trm cells. Our data demonstrate that in contrast to the other family members NR4A1 and NR4A2, NR4A3 is dispensable for the generation of CD8+ Trm cells in both epithelial and non-epithelial sites.

immunology↗

bioRxiv2024

Adoptive transfer of mitochondrial antigen-specific CD8+ T-cells in mice causes parkinsonism and compromises the dopamine system

The progressive degeneration of dopamine (DA) neurons drives motor symptoms in Parkinsons disease (PD). Whether this neuronal degeneration is due to cell-autonomous dysfunctions in DA neurons or to death signals generated by other cell types is a key problem to address. Recent evidence suggests that loss of function of the protein PINK1, linked to early-onset forms of PD, enhances the presentation of self-derived mitochondrial antigens, which induces the response of autoreactive CD8+ T cells. Whether mitochondrial antigen-specific CD8+ T cells alone are sufficient to induce nigrostriatal dysfunction has not been directly tested. Here we performed adoptive transfer of mitochondrial antigen-specific CD8+ T cells into wild-type or PINK1-deficient mice. We provide evidence for the entry and persistence of such cells in the brain and show that this leads to levodopa-reversible motor dysfunctions and partial degeneration of the nigrostriatal DA system in both genotypes. These findings establish that brain entry of autoreactive CD8+ T cells is sufficient to drive nigrostriatal degeneration and parkinsonian motor deficits, providing the most direct support to date for the hypothesis that an adaptive immune attack plays a key role in PD-like neurodegeneration.

neuroscience↗

bioRxiv2023

NR4A3 deficiency in CD8+ T cells improves adoptive T cell therapy of cancer

NR4A3 is a transcription factor that is rapidly induced in CD8+ T cells following antigenic recognition. We have previously shown that NR4A3 deficiency induces an early molecular program that promotes memory generation and enhances effector functions, which are two essential attributes for the success of adoptive cell therapy (ACT). Therefore, we tested the hypothesis that Nr4a3-/- CD8+ T cells would have outstanding efficacy in ACT of cancer. Our results show that ACT of melanoma-bearing mice with Nr4a3-/- effector CD8+ T cells provides a better tumor control than their wild-type counterpart. The therapeutic effect observed with Nr4a3-/- effector CD8+ T cells is even better than the one observed with ACT of Nr4a3+/+ effector CD8+ T cells in combination with anti-PD-L1 treatment. scRNA-seq analysis reveals a huge heterogeneity of tumor-infiltrating lymphocytes (TILs) states following ACT. The better tumor control observed with ACT of Nr4a3-/- CD8+ effectors without anti-PD-L1 treatment correlates with an enrichment of TILs within the clusters that are associated with the anti-PD-L1 response of wild-type TILs. Moreover, the clusters that are enriched in Nr4a3-/- TILs are the ones that are enriched for effector functions. Furthermore, Nr4a3-/- and Nr4a3+/+ effectors generate distinct progenitor populations. Pseudotime analysis suggests that these progenitors have different differentiation trajectories, which may explain why ACT with Nr4a3-/- effectors is more efficient. Therefore, modulation of NR4A3 activity may represent a new strategy to generate long-lived and highly functional T cells for ACT. One sentence summaryNR4A3 deficiency improves anti-tumor CD8+ T cell response

immunology↗

bioRxiv2022

Re-routing metabolism by the mitochondrial pyruvate carrier inhibitor MSDC-0160 attenuates neurodegeneration in a rat model of Parkinson's disease

BackgroundA growing body of evidence supports the idea that mitochondrial dysfunction might represent a key feature of Parkinsons disease (PD). Central regulators of energy production, mitochondria are also involved in several other essential functions such as cell death pathways and neuroinflammation which make them a potential therapeutic target for PD management. Interestingly, recent studies related to PD have reported a neuroprotective effect of targeting mitochondrial pyruvate carrier (MPC) by the insulin sensitizer MSDC-0160. As the sole point of entry of pyruvate into the mitochondrial matrix, MPC plays a crucial role in energetic metabolism which is impacted in PD. This study therefore aimed at providing insights into the mechanisms underlying the neuroprotective effect of MSDC-0160. MethodsWe investigated behavioral, cellular and metabolic impact of chronic MSDC-0160 treatment in unilateral 6-OHDA PD rats. We evaluated mitochondrial related processes through the expression of pivotal mitochondrial enzymes in dorsal striatal biopsies and the level of metabolites in serum samples using nuclear magnetic resonance spectroscopy (NMR)-based metabolomics. ResultsMSDC-0160 treatment in unilateral 6-OHDA rats improved motor behavior, decreased dopaminergic denervation and reduced mTOR activity and neuroinflammation. Concomitantly, MSDC-0160 administration strongly modified energy metabolism as revealed by increased ketogenesis, beta oxidation and glutamate oxidation to satisfy energy needs and maintain energy homeostasis. ConclusionMSDC-0160 exerts its neuroprotective effect through reorganization of multiple pathways connected to energy metabolism.

neuroscience↗

bioRxiv2021

Hypodopaminergic state of the nigrostriatal pathway drives compulsive alcohol use

The neurobiological mechanisms underlying compulsive alcohol use, a cardinal feature of alcohol use disorder, remain elusive. The key modulator of motivational processes dopamine (DA) is suspected to play an important role in this pathology, but its exact implication remains to be determined. Here, we found that rats expressing compulsive alcohol-related behavior, operationalized as punishment-resistant self-administration, showed a decrease in DA levels restricted to the dorsolateral territories of the striatum, the main output structure of the nigrostriatal DA pathway. We then causally demonstrated that a chemogenetic-induced selective hypodopaminergia of this pathway results in compulsive alcohol self-administration in rats otherwise resilient, accompanied by the emergence of alcohol withdrawal-like motivational impairments. These results demonstrate a major implication of tonic nigrostriatal hypodopaminergic state in alcohol addiction and provide new insights into our understanding of the neurobiological mechanisms underlying compulsive alcohol use.

neuroscience↗

bioRxiv2021

Early diagnosis of Parkinson's disease: A cross-species biomarker

BackgroundCare management of Parkinsons disease (PD) patients currently remains symptomatic, especially because diagnosis relying on the expression of the cardinal motor symptoms is made too late. Detecting PD earlier therefore represents a key step for developing therapies able to delay or slow down its progression. MethodsWe investigated metabolic markers in three different animal models of PD, mimicking different phases of the disease assessed by behavioral and histological evaluation, and in 2 cohorts of de novo PD patients (n = 95). Serum and brain tissue samples were analyzed by nuclear magnetic resonance spectroscopy and data submitted to advanced multivariate statistics. ResultsOur translational strategy reveals common metabolic dysregulations in serum of the different animal models and PD patients. Some of them were mirrored in the tissue samples, possibly reflecting pathophysiological mechanisms associated with PD development. Interestingly, some metabolic dysregulations appeared before motor symptom emergence, and could represent early biomarkers of PD. Finally, we built a composite biomarker with a combination of 6 metabolites. This biomarker discriminated animals mimicking PD from controls, even from the first, non-motor signs and very interestingly, also discriminated PD patients from healthy subjects. ConclusionFrom our translational study which included three animal models and two PD patient cohorts, we propose a promising composite biomarker exhibiting a high level of predictivity for PD diagnosis in its early phase, before motor symptoms appearance. FundingsANR, DOPALCOMP, Institut National de la Sante et de la Recherche Medicale, Grenoble Alpes University.

pathology↗

bioRxiv2020

Bilateral but not unilateral subthalamic stimulation promotes apathy: a translational study in rodents and Parkinson's disease patients

Apathy, depression, and anxiety represent the main neuropsychiatric symptoms of Parkinsons disease (PD). How subthalamic nucleus deep brain stimulation (STN-DBS) influences these symptoms, especially apathy, is a controversial topic. The present translational study investigates and compares the effect of bilateral or unilateral STN-DBS on this neuropsychiatric triad, combining a pre-clinical approach in rodents and a clinical follow-up of patients with PD. While depression and anxiety related behaviors remain unchanged, bilateral but not unilateral STN-DBS consistently induces apathy in patients and a reward seeking deficit in rodents. Together, these data substantiate the claim that STN-DBS may induce apathy by itself and suggest that bilateral but not the unilateral stimulation might be a critical factor.

neuroscience↗