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T lymphocytes are key players in CNS immunity, with distinct subgroups that work in a highly dynamic and, sometimes, antagonistic manner depending on the disorder. This review covers T-cell subgroups with a focus on pathogenic Th1 and Th17 cells and their role in mediating neuronal death and demyelination in multiple sclerosis (MS) and stroke, as well as the neurotoxic nature of CD8+ cytotoxic T lymphocytes and the neuroprotective and immunosuppressive roles of regulatory T cells (Tregs) that promote CNS homeostasis. In answer to the overwhelming need for effective pharmacotherapy, we overview of available pharmacotherapies that have the potential to target the aforementioned T-cell subsets. Treatments ultimately include broad-spectrum immunosuppressants, highly specific monoclonal antibodies, and new small-molecule inhibitors. Clinical data are added whenever possible to assess how these therapies interact with T-cell activity to restore immune balance in the CNS. This review highlights the evolution of treatment progress and the growing paradigm shift towards precision medicine through the targeting of T-cell subsets in neuroinflammatory diseases.<\/jats:p>","DOI":"10.1007\/s10787-025-01955-z","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T10:49:57Z","timestamp":1758710997000},"page":"5799-5818","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Beyond the blood\u2013brain barrier: unraveling T cell subsets in CNS immunity and disease"],"prefix":"10.1007","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5221-4666","authenticated-orcid":false,"given":"Mustafa M.","family":"Shokr","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,24]]},"reference":[{"key":"1955_CR1","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/J.NEUROSCIENCE.2025.06.037","volume":"580","author":"AT Aborode","year":"2025","unstructured":"Aborode AT, Adesola RO, Scott GY et al (2025) Role of blood-brain barrier in bacterial translocation. 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