CD4 ⁺ Trm sustain the chronic phase of auto-immune neuroinflammatory disease

Therapeutic options against multiple sclerosis (MS) preventing T cell migration to the central nervous system (CNS) have remarkable clinical effects against the relapsing-remitting (RRMS) form of the disease, while they are poorly effective against its progressive form (PMS). Disability progression in PMS is thought to result from an interplay between smoldering local inflammation and neurodegeneration. We postulated that an ongoing inflammatory process mediated by CNS-resident memory CD4 ⁺ T cells (CD4 ⁺ Trm) could contribute to promote disease chronicity independently of de novo recruitment of peripheral autoreactive T cells. Indeed, our results revealed the presence of bona fide CD4 ⁺ Trm expressing CD69, CXCR6, P2RX7, CD49a and the transcription factor Hobit in the CNS of mice with chronic experimental autoimmune encephalomyelitis (EAE) and in the brain of persons with PMS. Single-cell transcriptional analysis uncovered their transcriptional heterogeneity and inflammatory potential and, accordingly, CD4 ⁺ Trm preferentially localized within inflammatory lesions. Finally, depletion of both the recirculating and the CNS-resident CD4 ⁺ T cell compartments was required to alleviate neurological signs during the chronic phase of EAE. Our results, therefore, indicate that CD4 ⁺ Trm actively contribute to maintain a chronic inflammatory state in the CNS, promoting damage and/or preventing repair, and suggest that new therapeutic strategies for the treatment of PMS should consider targeting the CNS-resident T cell compartment.