A change of PD-1/PD-L1 expression on peripheral T cell subsets correlates with the different stages of Alzheimer's...

Immune checkpoints are a set of costimulatory and inhibitory molecules that maintain self-tolerance and regulate immune homeostasis. The expression of immune checkpoints on T cells in malignancy, chronic inflammation, and neurodegenerative diseases has gained increasing attention.

To characterize immune checkpoints in neurodegenerative diseases, we aimed to examine the expression of the immune checkpoint PD-1/PD-L1 in peripheral T cells in different Alzheimer's disease (AD) patients. To achieve this aim, sixteen AD patients and sixteen age-matched healthy volunteers were enrolled to analyze their CD3⁺ T cells, CD3⁺CD56⁺ (neural cell adhesion molecule, NCAM) T cells, CD4⁺/CD8⁺ T cells, and CD4⁺/CD8⁺CD25⁺ (interleukin-2 receptor alpha, IL-2RA) T cells in this study. The expression of PD-1 on T cells was similar between the AD patients and healthy volunteers, but increased expression of PD-L1 on CD3⁺CD56⁺ T cells (natural killer T cells, NKT-like), CD4⁺ T cells (helper T cells, Th), CD4⁺CD25⁺ T cells, and CD8⁺ T cells (cytotoxic T lymphocytes, CTL) was detected in the AD patients. In addition, we found negative correlations between the AD patients' cognitive performance and both CD8⁺ T cells and CD8⁺CD25⁺ T cells. To identify CD8⁺ T-cell phenotypic and functional characteristic differences between the healthy volunteers and AD patients in different stages, a machine learning algorithm, t-distributed stochastic neighbor embedding (t-SNE), was implemented. Using t-SNE enabled the above high-dimensional data to be visualized and better analyzed. The t-SNE analysis demonstrated that the cellular sizes and densities of PD-1/PD-L1 on CD8⁺ T cells differed among the healthy, mild AD, and moderate AD subjects.

Our results suggest that changes in PD-1/PD-L1-expressing T cells in AD patients' peripheral blood could be a potential biomarker for monitoring disease and shed light on the AD disease mechanism. Moreover, these findings indicate that PD-1/PD-L1 blockade treatment could be a novel choice to slow AD disease deterioration.