Bidirectional disruption of Lrrk2 function drives T cell dysregulation and an exhaustion-like immune response

Background: Neurodegenerative diseases including Parkinson's disease (PD) are increasingly associated with dysfunction in both central and peripheral immune systems. Pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2) represent a major cause of familial PD, while common polymorphisms are associated with inflammatory diseases. Methods: Here, using immunophenotyping flow cytometry and quantitative PCR (qPCR), we compared immune cell populations and function across both the central and peripheral immune systems in C57BL/6J wild type (WT), Lrrk2 p.G2019S knock-in (GKI) and Lrrk2 knock-out (LKO) models in basal and ex vivo immune-stimulated conditions. Results: With a focus on T cell biology, compared to their WT counterparts at baseline, GKI mice exhibit higher populations of Cd8+ and TH17 T cell subsets in the brain, whereas LKO mice exhibited unique central memory (TCM), follicular helper (TFH), and TH2 lineages. In the periphery, GKI mice demonstrated higher TH1, TH2, and TH17 subset expansions, whereas peripheral alterations in LKO are largely restricted to TH17 subsets. Within mutant genotypes, a striking discrepancy was observed between baseline gene expression and the translated proteins encoded, that reveals a fundamental loss of basal immune homeostasis. This phenomenon was further exposed following an acute (6-hour) ex vivo lipopolysaccharide (LPS) immune challenge. Following stimulation, GKI immune cells had reduced transcription, alongside stalled translation, for almost all effector molecules examined, while LKO immune cells had fewer transcriptional changes compared to wild type. Overall, both mutant lines had stalled or flatline effector molecule production after immune stimulation, suggesting a profound loss of functional responsiveness. This hypothesis was supported by a significant increase in surface protein of the inhibitory receptor Pd-1 on regulatory T cells (TREG) and TH1/TH2 Cd4+ T cell subsets in GKI mice. LKO immune landscapes trended toward similar exhaustion patterns, albeit less evident. Conclusions: These data suggest that bidirectional disruptions to normal Lrrk2 function break immune homeostasis. Immune cell function should be carefully considered when targeting LRRK2 kinase activity in patients with PD.