Tissue-resident memory CD4+ T cells sustain chronic CNS autoimmunity

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. The mechanisms sustaining the chronicity of PMS are poorly understood. Here, we investigated the role of tissue-resident memory CD4+ T (CD4+ Trm) cells in sustaining a chronic autoimmune process in the CNS. Our results revealed the presence of bona fide CD4+ Trm cells 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 patients with PMS. Single-cell transcriptomic analysis uncovered the transcriptional heterogeneity and inflammatory potential of CD4+ Trm cells and, accordingly, these cells 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 indicate that CD4+ Trm cells 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. Overall design: A CITE-seq analysis was performed on conventional CD4+ T cells isolated from the brain and spinal cord of mice during both the acute (day 14) and the chronic phase (day 50) of experimental autoimmune encephalomyelitis (EAE).