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Identification of genetic risk variants related to innate\/adaptive immunity have highlighted a role for neuroinflammation and neuroimmune interactions in FTLD. Studies have shown microglial and astrocyte activation together with T cell infiltration in the brain of THY-Tau22 tauopathy mice. However, this remains to be confirmed in FTLD-tau patients. We conducted a detailed post-mortem study of FTLD-tau cases including 45 progressive supranuclear palsy with clinical frontotemporal dementia, 33 Pick\u2019s disease, 12 FTLD-MAPT and 52 control brains to characterize the link between phosphorylated tau (pTau) epitopes and the innate and adaptive immunity. Tau pathology was assessed in the cerebral cortex using antibodies directed against: Tau-2 (phosphorylated and unphosphorylated tau), AT8 (pSer202\/pThr205), AT100 (pThr212\/pSer214), CP13 (pSer202), PHF1 (pSer396\/pSer404), pThr181 and pSer356. The immunophenotypes of microglia and astrocytes were assessed with phenotypic markers (Iba1, CD68, HLA-DR, CD64, CD32a, CD16 for microglia and GFAP, EAAT2, glutamine synthetase and ALDH1L1 for astrocytes). The adaptive immune response was explored via CD4+ and CD8+ T cell quantification and the neuroinflammatory environment was investigated via the expression of 30 inflammatory-related proteins using V-Plex Meso Scale Discovery.<\/jats:p>\n                  <jats:p>As expected, all pTau markers were increased in FTLD-tau cases compared to controls. pSer356 expression was greatest in FTLD-MAPT cases versus controls (P &amp;lt; 0.0001), whereas the expression of other markers was highest in Pick\u2019s disease. Progressive supranuclear palsy with frontotemporal dementia consistently had a lower pTau protein load compared to Pick\u2019s disease across tau epitopes. The only microglial marker increased in FTLD-tau was CD16 (P = 0.0292) and specifically in FTLD-MAPT cases (P = 0.0150). However, several associations were detected between pTau epitopes and microglia, supporting an interplay between them. GFAP expression was increased in FTLD-tau (P = 0.0345) with the highest expression in Pick\u2019s disease (P = 0.0019), while ALDH1L1 was unchanged. Markers of astrocyte glutamate cycling function were reduced in FTLD-tau (P = 0.0075; Pick\u2019s disease: P &amp;lt; 0.0400) implying astrocyte reactivity associated with a decreased glutamate cycling activity, which was further associated with pTau expression. Of the inflammatory proteins assessed in the brain, five chemokines were upregulated in Pick\u2019s disease cases (P &amp;lt; 0.0400), consistent with the recruitment of CD4+ (P = 0.0109) and CD8+ (P = 0.0014) T cells. Of note, the CD8+ T cell infiltration was associated with pTau epitopes and microglial and astrocytic markers. Our results highlight that FTLD-tau is associated with astrocyte reactivity, remarkably little activation of microglia, but involvement of adaptive immunity in the form of chemokine-driven recruitment of T lymphocytes.<\/jats:p>","DOI":"10.1093\/brain\/awad309","type":"journal-article","created":{"date-parts":[[2023,9,10]],"date-time":"2023-09-10T16:53:07Z","timestamp":1694364787000},"page":"590-606","source":"Crossref","is-referenced-by-count":60,"title":["Glial reactivity and T cell infiltration in frontotemporal lobar degeneration with tau pathology"],"prefix":"10.1093","volume":"147","author":[{"given":"Iain J","family":"Hartnell","sequence":"first","affiliation":[{"name":"Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton , Southampton SO16 6YD , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Declan","family":"Woodhouse","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Sciences, Faculty of Medicine, 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University of Southampton , Southampton SO16 6YD , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie C","family":"Lau","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Sciences, Faculty of Medicine, Sir Henry Wellcome Laboratories, University of Southampton , Southampton O16 6YD , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanette L","family":"Norman","sequence":"additional","affiliation":[{"name":"Histochemistry Research Unit, Clinical and Experimental Sciences, Faculty of Medicine University of Southampton, Southampton SO16 6YD , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S","family":"Chatelet","sequence":"additional","affiliation":[{"name":"Biomedical Imaging Unit, University Hospital Southampton NHS Trust , Southampton SO16 6YD , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6261-4230","authenticated-orcid":false,"given":"Luc","family":"Buee","sequence":"additional","affiliation":[{"name":"University of Lille, Inserm, CHU Lille, UMR-S1172\u2014Lille Neurosciences and Cognition , Lille 59045 , France"},{"name":"Alzheimer and Tauopathies, LabEX DISTALZ , Lille 59000 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A R","family":"Nicoll","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton , Southampton SO16 6YD , UK"},{"name":"Department of Cellular Pathology, University Hospital Southampton NHS Trust , Southampton SO16 6YD , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Blum","sequence":"additional","affiliation":[{"name":"University of Lille, Inserm, CHU Lille, UMR-S1172\u2014Lille Neurosciences and Cognition , Lille 59045 , France"},{"name":"Alzheimer and Tauopathies, LabEX DISTALZ , Lille 59000 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5763-3632","authenticated-orcid":false,"given":"Guillaume","family":"Dorothee","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton , Southampton SO16 6YD , UK"},{"name":"Sorbonne Universit\u00e9, Inserm, Centre de Recherche Saint-Antoine, CRSA, Immune System and Neuroinflammation Laboratory, H\u00f4pital Saint-Antoine , Paris 75012 , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5884-130X","authenticated-orcid":false,"given":"Delphine","family":"Boche","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton , Southampton SO16 6YD , 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