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

Paraneoplastic cerebellar degeneration associated with anti-Yo antibodies (Yo-PCD) is a rare neurological syndrome affecting patients with breast and gynecological cancers. Although T cell–mediated immune responses against Purkinje cell antigens are thought to drive neuronal injury, the cellular mechanisms underlying disease remain poorly understood. We aimed to define the immune landscape associated with this disorder across the blood and central nervous system. We performed single-cell RNA sequencing with paired T-cell receptor sequencing on immune cells isolated from blood and cerebrospinal fluid from six patients with Yo-PCD. Samples from individuals with multiple sclerosis, idiopathic intracranial hypertension and patients with ovarian cancer without neurological disease served as additional controls. Immune cell states, clonal expansion, and compartment-specific transcriptional programs were analyzed. Patients with Yo-PCD exhibit impaired immune tolerance programs in myeloid cells and regulatory T cells, including reduced expression of the transforming growth factor-β pathway. Myeloid cells display distinct compartment-specific activation states, with major histocompatibility complex class I programs in blood and class II in cerebrospinal fluid. Moreover, cytotoxic CD4-positive T cells, are selectively clonally expanded in cerebrospinal fluid, span progressive differentiation states, and share T-cell receptor clonotypes with CD4 T cells, consistent with local functional reprogramming. These findings identify compartmentalized immune responses as a defining feature of Yo-PCD and establish cytotoxic CD4-positive T cells as candidate mediators of disease. This work provides a baseline for developing biomarkers and immune-targeted therapeutic strategies in this devastating neurological disorder. Paraneoplastic cerebellar degeneration is a rare disease in which the body’s immune system attacks the cerebellum, a part of the brain that controls balance and coordination. It can develop in some people with breast or gynecological cancers, but the reasons are not well understood. In this study, we examined individual immune cells from blood and from the cerebrospinal fluid, the fluid surrounding the brain and spinal cord in patients with this disease. We compared these cells with those from patients with ovarian cancer without neurological disease, as well as from people with multiple sclerosis or intracranial hypertension. We found that cancer-related inflammation was present in patients with both cancers, but only those with paraneoplastic cerebellar degeneration showed signs that the normal mechanisms controlling immune responses had broken down. They also had a type of immune cell called cytotoxic CD4 T cells that accumulated in the cerebrospinal fluid and may contribute to damage of the cerebellum. Our findings provide new insight into why the immune system attacks the brain in this disease and highlight cytotoxic CD4 T cells as potential targets for future treatments. Petitpré, Tran, Wucher et al., use single-cell RNA and T-cell receptor sequencing of blood and cerebrospinal fluid immune cells from patients with anti-Yo paraneoplastic cerebellar degeneration to define the disease-associated immune landscape. They find impaired immune tolerance, distinct immune responses in blood and the nervous system, and expansion of cytotoxic CD4 T cells that may drive disease.