CNS immune remodelling in SLE associated with anti-CD19 CAR-T therapy

Objectives
Autologous anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy shows promise for refractory systemic lupus erythematosus (SLE), but its impact on central nervous system (CNS) immune remodelling and the cellular features associated with CAR-T–associated neurotoxicity remains unclear.
Methods
We performed integrated single‑cell RNA/T-cell receptor (TCR) sequencing and Olink proteomics on cerebrospinal fluid (CSF) from patients with SLE treated longitudinally with CAR‑T therapy (baseline n = 2, D9 n = 4, D60 n = 5), plus independent baseline single-cell RNA sequencing (n = 2) and Olink samples (n = 3).
Results
Single-cell profiling of 47,222 CSF cells showed dynamic CNS immune composition following CAR-T therapy, with notable changes in T cells. CAR-T cells were detected in the CNS and displayed predominantly proliferative and cytotoxic states at D9, whereas memory- and exhaustion-associated states predominated at D60. Endogenous CD8⁺ T cells exhibited diverse effector subsets at day 9, including granzyme B (GZMB)⁺, natural killer–like, type I interferon (IFN)–responsive, and human leukocyte antigen (HLA)⁺ granzyme H (GZMH)⁺ populations, followed by predominance of memory and proliferating subsets at day 60. CD4⁺ T cells at day 9 were enriched for type I IFN signalling. Ligand–receptor analysis showed extensive interactions between myeloid populations and lymphocytes. TCR analysis showed changes in clonal diversity and dynamics following treatment.
Conclusions
These findings suggest an association between CAR-T therapy and CNS immune remodelling in SLE, and provide cellular and molecular observations that may inform future studies of CNS immunity.