Ex vivo activation unmasks a sex-convergent, exhaustion-associated CD8+ T cell expansion in Parkinson's disease

Parkinson's disease (PD) impacts approximately 6.4 million males and 5.3 million females globally, yet lacks a validated peripheral biomarker. Blood samples are a more accessible alternative to brain tissue in living patients, but prior studies have predominantly analyzed immune cells in a static, resting-state, thereby missing functional differences that become apparent under challenge.

To better understand disease-associated dysfunction and its potential sex-related influence, researchers employed ex vivo PMA/ionomycin stimulation as a controlled functional stimulus, profiling 195,000 peripheral blood mononuclear cells (PBMCs) from 84 samples of 14 PD patients and 14 controls using single-cell RNA sequencing across an activation time course (0 hours, 2 hours, 4 hours), while stratifying data by sex throughout.

The findings revealed that sex explained more transcriptional variance than disease status, and male and female PD patients exhibited largely divergent responses at rest. However, upon peak activation, both groups converged on a distinct CD8+ effector memory T cell subpopulation (Tem-CD8). This subpopulation exhibited an exhaustion-associated program, characterized by a failure to resolve AP-1 induction and a reduction in inferred intercellular communication.

Consequently, the peripheral immune phenotype in PD patients is better characterized as an activation-dependent response rather than a fixed resting-state signature. This discovery identifies Tem-CD8 exhaustion as a potential disease-associated, sex-convergent biomarker for further investigation.