Compartmentalized cytotoxic CD4 + T cell responses in anti-Yo paraneoplastic cerebellar degeneration

International audience ; Paraneoplastic cerebellar degeneration with anti-Yo antibodies (Yo-PCD) is a rare neurological disorder associated with breast and gynecological cancers. Although T cell–mediated immunity against Purkinje cell antigens CDR2/CDR2L has been implicated, the precise mechanisms remain undefined. Here, we applied single-cell RNA sequencing and paired T cell receptor profiling to cerebrospinal fluid (CSF) and peripheral blood mononuclear cells (PBMCs) from six Yo-PCD patients and five ovarian cancer patients without paraneoplastic disease, with additional controls from individuals with multiple sclerosis or idiopathic intracranial hypertension. PBMCs from both cancer cohorts exhibited pro-inflammatory signatures. However, uniquely in Yo-PCD, antigen-presenting cells (APCs) and regulatory T cells showed reduced expression of tolerance-associated genes, including key components of the TGF-β pathway. Moreover, Yo-PCD APCs showed compartment-specific programs, with peripheral APCs enriched for MHC-I and inflammatory mediators, whereas CSF APCs upregulated MHC-II and interferon-stimulated genes. Yo-PCD CSF subclustering revealed no disease-specific expansion of CD8⁺ T cells. In contrast, CD4⁺ cytotoxic T cells were clonally expanded, spanned graded cytotoxic states, expressed central nervous system homing signatures, and overlapped with helper T cell clones, consistent with local reprogramming. Supporting their pathological relevance, CD4⁺ granzyme B⁺ T cells were identified in patient cerebellar tissue. Together, these findings define a dual-compartment immunopathology in Yo-PCD, highlighting CD4⁺ cytotoxic T cells as biomarkers and therapeutic targets.