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

Elemeery, M. N.; Tchung, A.; Boulet, S.; Mukherjee, S.; Giguere, N.; Daudelin, J.-F.; Hetu-Arbour, R.; Matheoud, D.; STRATTON, J. A.; Labrecque, N.; Trudeau, L.-E.

doi:10.1101/2024.02.26.582098

bioRxiv · 10.1101/2024.02.26.582098

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

Elemeery, M. N.·Tchung, A.·Boulet, S.·Mukherjee, S.·Giguere, N.·Daudelin, J.-F.·Hetu-Arbour, R.·Matheoud, D.·STRATTON, J. A.·Labrecque, N.·Trudeau, L.-E.

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Abstract

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.

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Elemeery, M. N., Tchung, A., Boulet, S., Mukherjee, S., Giguere, N., Daudelin, J.-F., Hetu-Arbour, R., Matheoud, D., STRATTON, J. A., Labrecque, N., Trudeau, L.-E.. 2024-02-28. Adoptive transfer of mitochondrial antigen-specific CD8+ T-cells in mice causes parkinsonism and compromises the dopamine system. https://doi.org/10.1101/2024.02.26.582098

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