Biology subjects

Daudelin, J.-F.

Publications and source records attributed to Daudelin, J.-F..

3 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↗