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

Abstract

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. 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). 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. 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.