CXCL13⁺ CD4⁺ T cells are associated with B-cell recruitment and lesion progression in cerebral cavernous...

Cerebral cavernous malformations (CCMs) are neurovascular abnormalities associated with lifelong risks of intracranial hemorrhage (ICH), seizures, and neurologic deficits, affecting approximately 0.16%~0.8% of the general population. Although immune cell infiltration is well recognized as promoting CCM progression, the mechanisms underlying their recruitment into the lesion microenvironment remain poorly understood. In our study, we employed single-cell RNA sequencing (scRNA-seq) to identify a significant enrichment of a CD4⁺ T-cell subset producing CXCL13 and decipher the cellular crosstalk within CCMs. The CXCL13-producing CD4⁺ T cells exhibited enhanced interaction with CXCR5⁺ memory B cells, which showed upregulation of genes related to activation, persistence, and targeted migration. Immunohistochemical staining supported the spatial co-localization between CXCL13⁺ CD4⁺ T cells and CXCR5⁺ CD20⁺ B cells, as well as a positive association between their abundances, reinforcing this cellular crosstalk and suggesting a potential role for CXCL13 in shaping the inflammatory microenvironment and local adaptive immune responses. Clinically, elevated CXCL13 expression in CCM lesions was associated with a higher frequency of subacute ICH and B-cell infiltration in patients. Finally, in vivo experiments showed that administration of recombinant CXCL13 increased B-cell infiltration and Prussian blue staining-defined lesion bleeding, whereas blockade of CXCL13 attenuated CCM lesion development. Thus, our study identified a potentially pathogenic CXCL13⁺ CD4⁺ T-cell subset in CCMs, providing a rationale for targeting CXCL13 signaling in CCMs.