Biology subjects

Labrecque, N.

Publications and source records attributed to Labrecque, N..

4 recordsLinked to original sources

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↗

bioRxiv2024

Modeling gene-environment interactions in Parkinson's Disease: Helicobacter pylori infection of Pink1-/- mice induces CD8 T cell-dependent motor and cognitive dysfunction.

Parkinsons disease (PD) is a chronic neurodegenerative disorder characterized by progressive loss of motor function. Diagnosis occurs late: after motor symptom development downstream of the irreparable loss of a large proportion of the dopaminergic neurons in the substantia nigra of the brain. Understanding PD pathophysiology in its pre-motor prodromal phase is needed for earlier diagnosis and intervention. Genetic risk factors, environmental triggers, and dysregulated immunity have all been implicated in PD development. Here, we demonstrate in a mouse model deficient in the PD-associated gene Pink, that infection with the human PD-associated gastric bacterium Helicobacter pylori leads to development of motor and cognitive signs resembling prodromal features of PD. This was also associated with proliferation and activation of primary mitochondria-reactive CD8 T cells and infiltration of CD8 T cells into the brain. Development of the motor and cognitive phenotypes in the infected Pink1-/- mice was abrogated when CD8 T cells were depleted prior to infection. We anticipate that this new model, which integrates genetic PD susceptibility, a PD-relevant environmental trigger, and specific immune changes that are required for symptom development, will be a valuable tool for increasing our understanding of this complex disease.

immunology↗

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↗