Characterisation of choroid plexus-infiltrating T cells reveals novel therapeutic targets in murine neuropsychiatric lupus

Erica Moore, Sushma Bharrhan, Deepak A. Rao, Fernando Macian, Chaim Putterman

Research output: Contribution to journalArticlepeer-review

Abstract

Objective Diffuse central nervous system manifestations, referred to as neuropsychiatric lupus (NPSLE), are observed in 20–40% of lupus patients and involve complex mechanisms that have not yet been adequately elucidated. In murine NPSLE models, choroid plexus (ChP)-infiltrating T cells have not been fully evaluated as drivers of neuropsychiatric disease. Method Droplet-based single-cell transcriptomic analysis (single-cell RNA sequencing) and immune T-cell receptor profiling were performed on ChP tissue from MRL/lpr mice, an NPSLE mouse model, at an’early’ and’late’ disease state, to investigate the infiltrating immune cells that accumulate with NPSLE disease progression. Results We found 19 unique clusters of stromal and infiltrating cells present in the ChP of NPSLE mice. Higher resolution of the T-cell clusters uncovered multiple T-cell subsets, with increased exhaustion and hypoxia expression profiles. Clonal analysis revealed that the clonal CD8+T cell CDR3 sequence, ASGDALGGYEQY, matched that of a published T-cell receptor sequence with specificity for myelin basic protein. Stromal fibroblasts are likely drivers of T-cell recruitment by upregulating the VCAM signalling pathway. Systemic blockade of VLA-4, the cognate ligand of VCAM, resulted in significant resolution of the ChP immune cell infiltration and attenuation of the depressive phenotype. Conclusion Our analysis details the dynamic transcriptomic changes associated with murine NPSLE disease progression, and highlights its potential use in identifying prospective lupus brain therapeutic targets.

Original languageEnglish
Article numberard-2023-224689
JournalAnnals of the Rheumatic Diseases
Early online date26 Mar 2024
DOIs
StatePublished - 15 Jul 2024

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