Tissue resident memory CD8+ T cells are present but not critical for demyelination and neurodegeneration in a mouse model of multiple system atrophy.

Corbin-Stein, N. J.; Childers, G. M.; Webster, J. M.; Zane, A.; Yang, Y.-T.; Ali, M. A.; Sandoval, I. M.; Manfredsson, F. J.; Kordower, J.; Tyrrell, D.; Harms, A. S.

doi:10.1101/2024.06.02.597035

bioRxiv · 10.1101/2024.06.02.597035

Tissue resident memory CD8+ T cells are present but not critical for demyelination and neurodegeneration in a mouse model of multiple system atrophy.

Corbin-Stein, N. J.·Childers, G. M.·Webster, J. M.·Zane, A.·Yang, Y.-T.·Ali, M. A.·Sandoval, I. M.·Manfredsson, F. J.·Kordower, J.·Tyrrell, D.·Harms, A. S.

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Abstract

Multiple system atrophy (MSA) is rare, fast progressing, and fatal synucleinopathy with alpha-synuclein (-syn) inclusions located within oligodendroglia called glial cytoplasmic inclusions (GCI). Along with GCI pathology there is severe demyelination, neurodegeneration, and neuroinflammation. In post-mortem tissue, there is significant infiltration of CD8+ T cells into the brain parenchyma, however their role in disease progression is unknown. To determine the role of CD8+ T cells, a modified AAV, Olig001-SYN, was used to selectively overexpress -syn in oligodendrocytes modeling MSA in mice. Four weeks post transduction, we observed significant CD8+ T cell infiltration into the striatum of Olig001-SYN transduced mice recapitulating the CD8+ T cell infiltration observed in post-mortem tissue. To understand the role of CD8+ T cells, a CD8 knockout mice were transduced with Olig001-SYN. Six months post transduction into a mouse lacking CD8+ T cells, demyelination and neurodegeneration were unchanged. Four weeks post transduction, neuroinflammation and demyelination were enhanced in CD8 knockout mice compared to wild type controls. Applying unbiased spectral flow cytometry, CD103+, CD69+, CD44+, CXCR6+, CD8+ T cells were identified when -syn was present in oligodendrocytes, suggesting the presence of tissue resident memory CD8+ T (Trm) cells during MSA disease progression. This study indicates that CD8+ T cells are not critical in driving MSA pathology but are needed to modulate the neuroinflammation and demyelination response.

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Corbin-Stein, N. J., Childers, G. M., Webster, J. M., Zane, A., Yang, Y.-T., Ali, M. A., Sandoval, I. M., Manfredsson, F. J., Kordower, J., Tyrrell, D., Harms, A. S.. 2024-06-03. Tissue resident memory CD8+ T cells are present but not critical for demyelination and neurodegeneration in a mouse model of multiple system atrophy.. https://doi.org/10.1101/2024.06.02.597035

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