Monocyte-derived cells promote transient insult-induced brain injury by enhancing CD8⁺ T cell response

Brain-infiltrating CD8⁺ T cells participate in the progression of diverse neurologic diseases, yet the mechanisms underlying their regulation remain unclear. Here, using single-cell RNA sequencing from patients with radiation-induced brain injury (RIBI), we find significant infiltration of conventional dendritic cell (cDC)2-like cells exhibiting transcriptional features of monocytes, along with professional antigen-presenting cell (APC) signatures. Lineage-tracing and monocyte-depletion experiments confirm their peripheral monocytic origin and important role in regulating the CD8⁺ T response. Single-cell T cell receptor (TCR) sequencing shows clonal expansion of infiltrating CD8⁺ T cells, which interact with cDC2-like cells through CD28^-CD80/CD86 co-stimulatory signals, as suggested by cell-cell communication analysis. Blocking CD80/CD86 broadly reduces the CD8⁺ T cell response and diminishes cognitive impairments. Similar mechanisms are shared in experimental stroke. Our findings highlight the infiltration of monocyte-derived cells, particularly monocyte-derived DCs, into injured brains and suggest their role in promoting CD8⁺ T cell-mediated neuropathology, providing a potential therapeutic target for transient insult-induced brain injury.