Tissue-resident memory CD4+ T cells infiltrate the CNS in progressive multiple sclerosis and contribute to chronic autoimmunity in mice

Preventing T cell migration to the central nervous system (CNS) has remarkable therapeutic effects in relapsing-remitting multiple sclerosis (RRMS) but is poorly effective against the progressive form (PMS). Disability progression in PMS likely results from an interplay between smoldering local inflammation and neurodegeneration. The mechanisms sustaining the chronicity of PMS are poorly understood. Here, we investigated the potential role of tissue-resident memory CD4⁺ T cells (CD4⁺ Trm cells) in sustaining chronic CNS autoimmunity. We showed that CD4⁺ Trm cells were present in the CNS of mice with chronic experimental autoimmune encephalomyelitis (EAE) and in brain tissues from persons with PMS. Using flow cytometry and immunohistofluorescence analysis, we revealed the presence of bona fide CD4⁺ Trm cells expressing characteristic Trm cell surface markers, including CD69, CXCR6, P2RX7, and CD49a, in the CNS of mice with EAE and in the brains of persons with PMS. These T cells also expressed the transcription factor Hobit in mice with chronic EAE. Single-cell transcriptomic analysis uncovered the transcriptional heterogeneity and inflammatory potential of CD4⁺ Trm cells, and, accordingly, these cells localized within CNS inflammatory lesions of mice with EAE and persons with PMS. Last, either genetic or pharmacological depletion of CD4⁺ Trm cells combined with antibody-mediated depletion of the recirculating CD4⁺ T cell compartment alleviated neurological signs during the chronic phase of EAE. Our results indicate that CD4⁺ Trm cells contribute to maintain a chronic inflammatory state in the CNS and suggest that therapeutic strategies for PMS should consider targeting the CNS-resident T cell compartment.