RESUMO
Inflammatory disorders of the CNS are frequently accompanied by synaptic loss, which is thought to involve phagocytic microglia and complement components. However, the mechanisms accounting for aberrant synaptic connectivity in the context of CD8+ T cell-driven neuronal damage are poorly understood. Here, we profiled the neuronal translatome in a murine model of encephalitis caused by CD8+ T cells targeting antigenic neurons. Neuronal STAT1 signaling and downstream CCL2 expression were essential for apposition of phagocytes, ensuing synaptic loss and neurological disease. Analogous observations were made in the brains of Rasmussen's encephalitis patients. In this devastating CD8+ T cell-driven autoimmune disease, neuronal STAT1 phosphorylation and CCL2 expression co-clustered with infiltrating CD8+ T cells as well as phagocytes. Taken together, our findings uncover an active role of neurons in coordinating phagocyte-mediated synaptic loss and highlight neuronal STAT1 and CCL2 as critical steps in this process that are amenable to pharmacological interventions.
Assuntos
Neurônios/metabolismo , Fagocitose/fisiologia , Sinapses/fisiologia , Animais , Encéfalo/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Quimiocina CCL2/genética , Quimiocina CCL2/fisiologia , Modelos Animais de Doenças , Encefalite/genética , Encefalite/imunologia , Encefalite/fisiopatologia , Feminino , Humanos , Inflamação/imunologia , Inflamação/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Doenças do Sistema Nervoso/metabolismo , Neurônios/fisiologia , Fagócitos/imunologia , Fagócitos/metabolismo , Fagocitose/imunologia , Fosforilação , Fator de Transcrição STAT1/fisiologia , Transcriptoma/genéticaRESUMO
Ependymal and choroid plexus tumours arise in anatomically related regions. Their intraoperative differential diagnosis is large and depends on factors such as age, tumour site and clinical presentation. Squash cytology can provide valuable information in this context. Cytological features of conventional ependymomas, subependymomas and myxopapillary ependymomas as well as choroid plexus tumours are reviewed and illustrated. Differential diagnostic considerations integrating morphological and clinical information are discussed.
Assuntos
Neoplasias do Plexo Corióideo , Ependimoma , Humanos , Neoplasias do Plexo Corióideo/patologia , Neoplasias do Plexo Corióideo/diagnóstico , Ependimoma/patologia , Ependimoma/diagnóstico , Citodiagnóstico/métodos , Diagnóstico Diferencial , Plexo Corióideo/patologia , Epêndima/patologia , FemininoRESUMO
Mutations affecting codon 172 of the isocitrate dehydrogenase 2 (IDH2) gene define a subgroup of sinonasal undifferentiated carcinomas (SNUCs) with a relatively favorable prognosis and a globally hypermethylated phenotype. They are also recurrent (along with IDH1 mutations) in gliomas, acute myeloid leukemia, and intrahepatic cholangiocarcinoma. Commonly reported mutations, all associated with aberrant IDH2 enzymatic activity, include R172K, R172S, R172T, R172G, and R172M. We present a case of SNUC with a never-before-described IDH2 mutation, R172A. Our report compares the methylation pattern of our sample to other cases from the Gene Expression Omnibus database. Hierarchical clustering suggests a strong association between our sample and other IDH-mutant SNUCs and a clear distinction between sinonasal normal tissues and tumors. Principal component analysis (PCA), using 100 principal components explaining 94.5% of the variance, showed the position of our sample to be within 1.02 standard deviation of the other IDH-mutant SNUCs. A molecular modeling analysis of the IDH2 R172A versus other R172 variants provides a structural explanation to how they affect the protein active site. Our findings thus suggest that the R172A mutation in IDH2 confers a gain of function similar to other R172 mutations in IDH2, resulting in a similar hypermethylated profile.
Assuntos
Carcinoma , Metilação de DNA , Isocitrato Desidrogenase , Neoplasias do Seio Maxilar , Mutação , Humanos , Isocitrato Desidrogenase/genética , Metilação de DNA/genética , Carcinoma/genética , Carcinoma/patologia , Neoplasias do Seio Maxilar/genética , Neoplasias do Seio Maxilar/patologia , Masculino , Pessoa de Meia-Idade , Feminino , IdosoRESUMO
Tumor cell fraction (TCF) estimation is a common clinical task with well-established large interobserver variability. It thus provides an ideal test bed to evaluate potential impacts of employing a tumor cell fraction computer-aided diagnostic (TCFCAD) tool to support pathologists' evaluation. During a National Slide Seminar event, pathologists (n = 69) were asked to visually estimate TCF in 10 regions of interest (ROIs) from hematoxylin and eosin colorectal cancer images intentionally curated for diverse tissue compositions, cellularity, and stain intensities. Next, they re-evaluated the same ROIs while being provided a TCFCAD-created overlay highlighting predicted tumor vs nontumor cells, together with the corresponding TCF percentage. Participants also reported confidence levels in their assessments using a 5-tier scale, indicating no confidence to high confidence, respectively. The TCF ground truth (GT) was defined by manual cell-counting by experts. When assisted, interobserver variability significantly decreased, showing estimates converging to the GT. This improvement remained even when TCFCAD predictions deviated slightly from the GT. The standard deviation (SD) of the estimated TCF to the GT across ROIs was 9.9% vs 5.8% with TCFCAD (P < .0001). The intraclass correlation coefficient increased from 0.8 to 0.93 (95% CI, 0.65-0.93 vs 0.86-0.98), and pathologists stated feeling more confident when aided (3.67 ± 0.81 vs 4.17 ± 0.82 with the computer-aided diagnostic [CAD] tool). TCFCAD estimation support demonstrated improved scoring accuracy, interpathologist agreement, and scoring confidence. Interestingly, pathologists also expressed more willingness to use such a CAD tool at the end of the survey, highlighting the importance of training/education to increase adoption of CAD systems.
Assuntos
Computadores , Patologistas , Humanos , SuíçaRESUMO
Glial cell activation is a hallmark of several neurodegenerative and neuroinflammatory diseases. During HIV infection, neuroinflammation is associated with cognitive impairment, even during sustained long-term suppressive antiretroviral therapy. However, the cellular subsets contributing to neuronal damage in the CNS during HIV infection remain unclear. Using post-mortem brain samples from eight HIV patients and eight non-neurological disease controls, we identify a subset of CNS phagocytes highly enriched in LGALS3, CTSB, GPNMB and HLA-DR, a signature identified in the context of ageing and neurodegeneration. In HIV patients, the presence of this phagocyte phenotype was associated with synaptic stripping, suggesting an involvement in the pathogenesis of HIV-associated neurocognitive disorder. Taken together, our findings elucidate some of the molecular signatures adopted by CNS phagocytes in HIV-positive patients and contribute to the understanding of how HIV might pave the way to other forms of cognitive decline in ageing HIV patient populations.
Assuntos
Infecções por HIV , Fagócitos , Sinapses , Encéfalo/patologia , Encéfalo/virologia , Infecções por HIV/complicações , Infecções por HIV/metabolismo , Infecções por HIV/patologia , Humanos , Glicoproteínas de Membrana , Transtornos Neurocognitivos , Neurônios/patologia , Neurônios/virologia , Fagócitos/metabolismo , Fagócitos/patologia , Sinapses/patologia , Sinapses/virologiaRESUMO
Transplantation of appropriate neuronal precursors after injury is a promising strategy to reconstruct cortical circuits, but the efficiency of these approaches remains limited. Here, we applied targeted apoptosis to selectively ablate layer II/III pyramidal neurons in the rat juvenile cerebral cortex and attempted to replace lost neurons with their appropriate embryonic precursors by transplantation. We demonstrate that grafted precursors do not migrate to replace lost neurons but form vascularized clusters establishing reciprocal synaptic contacts with host networks and show functional integration. These heterotopic neuronal clusters significantly enhance the activity of the host circuits without causing epileptic seizures and attenuate the apoptotic injury-induced functional deficits in electrophysiological and behavioral tests. Chemogenetic activation of grafted neurons further improved functional recovery, and the persistence of the graft was necessary for maintaining restored functions in adult animals. Thus, implanting neuronal precursors capable to form synaptically integrated neuronal clusters combined with activation-based approaches represents a useful strategy for helping long-term functional recovery following brain injury.
Assuntos
Lesões Encefálicas , Células-Tronco Embrionárias/transplante , Células-Tronco Neurais/transplante , Recuperação de Função Fisiológica/fisiologia , Transplante de Células-Tronco/métodos , Animais , Ratos , Ratos WistarRESUMO
Statins are widely prescribed in the treatment of hypercholesterolemia. While their efficacy in the secondary prevention of vascular events is proven, their safety profile in older patients with multiple co-morbidities and polypharmacy remains questionable. Although rare, antihydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) myopathy is a severe adverse effect of statins, manifesting as myalgias, proximal muscle weakness, muscle cell necrosis and rhabdomyolysis. We report an uncommon case of an autopsy-proven anti-HMGCR necrotising myopathy predominately affecting pharyngeal muscles in an older patient, leading to dysphagia, pneumonia and death within 3 weeks from onset. Clinicians should screen for dysphagia in any patient with suspected anti-HMGCR myopathy, order an anti-HMGCR antibody titre and consider prompt immunosupressive therapy.
Assuntos
Doenças Autoimunes , Inibidores de Hidroximetilglutaril-CoA Redutases , Doenças Musculares , Miosite , Idoso , Autoanticorpos , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/tratamento farmacológico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Doenças Musculares/induzido quimicamente , Doenças Musculares/diagnóstico , Músculos FaríngeosRESUMO
The spatial organization of vascular endothelial growth factor (VEGF) signaling is a key determinant of vascular patterning during development and tissue repair. How VEGF signaling becomes spatially restricted and the role of VEGF secreting astrocytes in this process remains poorly understood. Using a VEGF-GFP fusion protein and confocal time-lapse microscopy, we observed the intracellular routing, secretion and immobilization of VEGF in scratch-activated living astrocytes. We found VEGF to be directly transported to cell-extracellular matrix attachments where it is incorporated into fibronectin fibrils. VEGF accumulated at ß1 integrin containing fibrillar adhesions and was translocated along the cell surface prior to internalization and degradation. We also found that only the astrocyte-derived, matrix-bound, and not soluble VEGF decreases ß1 integrin turnover in fibrillar adhesions. We suggest that polarized VEGF release and ECM remodeling by VEGF secreting cells is key to control the local concentration and signaling of VEGF. Our findings highlight the importance of astrocytes in directing VEGF functions and identify these mechanisms as promising target for angiogenic approaches.
Assuntos
Astrócitos/metabolismo , Polaridade Celular/fisiologia , Matriz Extracelular/metabolismo , Transdução de Sinais/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Astrócitos/ultraestrutura , Polaridade Celular/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/citologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Hidrazonas/metabolismo , Antígeno Ki-67/metabolismo , Microscopia Confocal , Neurônios/metabolismo , Fotodegradação , Puromicina/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/genética , Proteínas de Ligação a Fator Solúvel Sensível a N-Etilmaleimida/metabolismo , Fatores de Tempo , TransfecçãoRESUMO
Immune-mediated necrotizing myopathy (IMNM) is a rare subtype of idiopathic inflammatory myopathy that is characterized by severe subacute proximal weakness, myofiber necrosis, and significantly elevated serum creatine kinase. Anti-signal recognition particle (SRP) and anti-3-hydroxy-3-methylglutaryl-coenzyme-A reductase autoantibodies have been found in about two-thirds of patients with IMNM. This myopathy is usually idiopathic and there is a scarce literature concerning its association with connective tissue diseases. Herein, we report an unusual case of a young woman who presented with both rheumatoid arthritis and severe anti-SRP IMNM. Thankfully to a therapeutic protocol combining rituximab and cyclophosphamide, an important improvement was achieved, and notably no serious side effect was observed.
Assuntos
Artrite Reumatoide , Doenças Autoimunes , Doenças Musculares , Miosite , Feminino , Humanos , Partícula de Reconhecimento de Sinal , Miosite/diagnóstico , Miosite/tratamento farmacológico , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológicoRESUMO
Posterior fossa atypical teratoid rhabdoid tumor (ATRT) is a rare childhood tumor usually associated with a dismal prognosis. Although upfront surgical gross total resection (GTR) has classically been the first line of treatment, new multimodal treatments, including two-stage surgery, are showing promising results in terms of overall survival (OS) and complication rate. We present a case of a 9-month-old child treated with two-staged surgery and chemotherapy. When deemed risky, multimodal treatments, including staged surgeries, can be a safe alternative to reduce surgical mortality and morbidity. At 23 months old, the patient had normal global development and no major impact on quality of life. We, therefore, discuss the most recent advancements from a treatment perspective, including molecular targeting.
RESUMO
Progressive multifocal leukoencephalopathy (PML) is a severe infection of the CNS occurring in immunocompromised individuals in which large demyelinating lesions are induced by polyomavirus JC (JCV). In the absence of effective antiviral treatment, control of the infection relies on restoring anti-JCV immunity. Thus, particularly in long-standing immunocompromising conditions such as organ transplantation, lymphoproliferative disorders, or idiopathic lymphopenia, new strategies to boost anti-JCV immune responses are needed. Here, we report the case of a patient developing PML in the context of kidney transplantation who received recombinant human interleukin 7 to foster immune responses against JCV. We give an overview of the immunologic mechanisms underlying the development of PML and immune restoration within the CNS after JCV infection. Immunotherapeutic strategies developed based on current understanding of the disease hold promise in managing patients with PML.
Assuntos
Vírus JC , Transplante de Rim , Leucoencefalopatia Multifocal Progressiva , Humanos , Leucoencefalopatia Multifocal Progressiva/terapia , Imunoterapia , Hospedeiro ImunocomprometidoRESUMO
OBJECTIVE: To evaluate ChatGPT's performance in brain glioma adjuvant therapy decision-making. METHODS: We randomly selected 10 patients with brain gliomas discussed at our institution's central nervous system tumour board (CNS TB). Patients' clinical status, surgical outcome, textual imaging information and immuno-pathology results were provided to ChatGPT V.3.5 and seven CNS tumour experts. The chatbot was asked to give the adjuvant treatment choice, and the regimen while considering the patient's functional status. The experts rated the artificial intelligence-based recommendations from 0 (complete disagreement) to 10 (complete agreement). An intraclass correlation coefficient agreement (ICC) was used to measure the inter-rater agreement. RESULTS: Eight patients (80%) met the criteria for glioblastoma and two (20%) were low-grade gliomas. The experts rated the quality of ChatGPT recommendations as poor for diagnosis (median 3, IQR 1-7.8, ICC 0.9, 95% CI 0.7 to 1.0), good for treatment recommendation (7, IQR 6-8, ICC 0.8, 95% CI 0.4 to 0.9), good for therapy regimen (7, IQR 4-8, ICC 0.8, 95% CI 0.5 to 0.9), moderate for functional status consideration (6, IQR 1-7, ICC 0.7, 95% CI 0.3 to 0.9) and moderate for overall agreement with the recommendations (5, IQR 3-7, ICC 0.7, 95% CI 0.3 to 0.9). No differences were observed between the glioblastomas and low-grade glioma ratings. CONCLUSIONS: ChatGPT performed poorly in classifying glioma types but was good for adjuvant treatment recommendations as evaluated by CNS TB experts. Even though the ChatGPT lacks the precision to replace expert opinion, it may serve as a promising supplemental tool within a human-in-the-loop approach.
Assuntos
Neoplasias Encefálicas , Glioma , Humanos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Inteligência Artificial , Glioma/patologia , Glioma/cirurgia , Tomada de DecisõesRESUMO
PURPOSE: Transsphenoidal surgery for non-functioning pituitary adenomas (NFPAs) can alter pituitary function. We assessed the rates of improvement and deterioration of pituitary function by axis and searched for predictive factors of these outcomes. METHODS: We reviewed consecutive medical files from patients having had transsphenoidal surgery for NFPA between 2004 and 2018. Pituitary functions and MRI imaging were analyzed prior and after surgery. The occurrence of recovery and new deficit were documented per axis. Prognostic factors of hormonal recovery and new deficits were searched. RESULTS: Among 137 patients analyzed, median tumor size of the NFPA was 24.8 mm and 58.4% of patients presented visual impairment. Before surgery, 91 patients (67%) had at least one abnormal pituitary axis (hypogonadism: 62.4%; hypothyroidism: 41%, adrenal insufficiency: 30.8%, growth hormone deficiency: 29.9%; increased prolactin: 50.8%). Following surgery, the recovery rate of pituitary deficiency of one axis or more was 46% and the rate of new pituitary deficiency was 10%. Rates of LH-FSH, TSH, ACTH and GH deficiency recovery were 35.7%, 30.4%, 15.4%, and 45.5% respectively. Rates of new LH-FSH, TSH, ACTH and GH deficiencies were 8.3%, 1.6%, 9.2% and 5.1% respectively. Altogether, 24.6% of patients had a global pituitary function improvement and only 7% had pituitary function worsening after surgery. Male patients and patients with hyperprolactinemia upon diagnosis were more likely to experience pituitary function recovery. No prognostic factors for the risk of new deficiencies were identified. CONCLUSION: In a real-life cohort of patients with NFPAs, recovery of hypopituitarism after surgery is more frequent than the occurrence of new deficiencies. Hence, hypopituitarism could be considered a relative indication for surgery in patients with NFPAs.
Assuntos
Hipopituitarismo , Neoplasias Hipofisárias , Humanos , Masculino , Hipófise/diagnóstico por imagem , Hipófise/cirurgia , Hipófise/patologia , Hipopituitarismo/epidemiologia , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/cirurgia , Neoplasias Hipofisárias/patologia , Hormônio Foliculoestimulante , Tireotropina , Hormônio AdrenocorticotrópicoRESUMO
Neuroinflammation causes neuronal injury in multiple sclerosis (MS) and other neurological diseases. MicroRNAs (miRNAs) are important modulators of neuronal stress responses, but knowledge about their contribution to neuronal protection or damage during inflammation is limited. Here, we constructed a regulatory miRNA-mRNA network of inflamed motor neurons by leveraging cell type-specific miRNA and mRNA sequencing of mice undergoing experimental autoimmune encephalomyelitis (EAE). We found robust induction of miR-92a in inflamed spinal cord neurons and identified cytoplasmic polyadenylation element-binding protein 3 (Cpeb3) as a key target of miR-92a-mediated posttranscriptional silencing. We detected CPEB3 repression in inflamed neurons in murine EAE and human MS. Moreover, both miR-92a delivery and Cpeb3 deletion protected neuronal cultures against excitotoxicity. Supporting a detrimental effect of Cpeb3 in vivo, neuron-specific deletion in conditional Cpeb3 knockout animals led to reduced inflammation-induced clinical disability in EAE. Together, we identified a neuroprotective miR-92a-Cpeb3 axis in neuroinflammation that might serve as potential treatment target to limit inflammation-induced neuronal damage.
Assuntos
Encefalomielite Autoimune Experimental , MicroRNAs , Esclerose Múltipla , Humanos , Camundongos , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Doenças Neuroinflamatórias , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/metabolismo , Inflamação/genética , Inflamação/metabolismo , Neurônios/metabolismo , RNA Mensageiro/metabolismo , Camundongos Endogâmicos C57BL , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismoRESUMO
BACKGROUND: Mitotic deregulations may contribute significantly to cell division errors and the development of aggressive tumor cells. The mitotic kinase Aurora B is essential for chromosome segregation. Its gene is located at 17p13 in close proximity to the TP53 gene. Although the frequent alteration of this locus is well known, the information about the AURKB status and protein expression is limited. METHODS: 50 breast carcinoma cases were evaluated for 17p13 status and chromosome 17 ploidy by FISH and for Aurora B protein by immunohistochemistry. RESULTS: Aurora B protein expression showed a strong correlation with cell proliferation (regression coefficient = 0.77). Therefore, the Aurora B/MIB-1 index was used as a measure of expression, which showed a wide range (1-35%, mean 0.32, SD ± 0.28). A gain in the 17p13 chromosome locus could not be shown while a deletion was stated in 10/50 cases including a subset with TP53 and AURKB codeletion in 6/10 cases. The loss of TP53/AURKB loci strongly correlated with aneusomy (p < 0.0001). CONCLUSION: Elevated Aurora B expression frequently occurs due to an increased cell proliferation rate in breast carcinoma. Codeletion of TP53 and AURKB at 17p13 indicates a concerted mechanism leading to the survival of cell clones with deficient mitotic kinase function which could contribute to the formation of aneuploid cells and an aggressive tumor phenotype.
Assuntos
Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/genética , Genes p53/genética , Proteínas Serina-Treonina Quinases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Aneuploidia , Aurora Quinase B , Aurora Quinases , Neoplasias da Mama/enzimologia , Carcinoma Ductal de Mama/enzimologia , Carcinoma Lobular/enzimologia , Ciclo Celular , Proliferação de Células , Cromossomos Humanos Par 17/genética , Variações do Número de Cópias de DNA , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Antígeno Ki-67/metabolismo , Pessoa de Meia-Idade , Fenótipo , Proteínas Serina-Treonina Quinases/metabolismoRESUMO
Neuroinflammation leads to neuronal stress responses that contribute to neuronal dysfunction and loss. However, treatments that stabilize neurons and prevent their destruction are still lacking. Here, we identify the histone methyltransferase G9a as a druggable epigenetic regulator of neuronal vulnerability to inflammation. In murine experimental autoimmune encephalomyelitis (EAE) and human multiple sclerosis (MS), we found that the G9a-catalyzed repressive epigenetic mark H3K9me2 was robustly induced by neuroinflammation. G9a activity repressed anti-ferroptotic genes, diminished intracellular glutathione levels, and triggered the iron-dependent programmed cell death pathway ferroptosis. Conversely, pharmacological treatment of EAE mice with a G9a inhibitor restored anti-ferroptotic gene expression, reduced inflammation-induced neuronal loss, and improved clinical outcome. Similarly, neuronal anti-ferroptotic gene expression was reduced in MS brain tissue and was boosted by G9a inhibition in human neuronal cultures. This study identifies G9a as a critical transcriptional enhancer of neuronal ferroptosis and potential therapeutic target to counteract inflammation-induced neurodegeneration.
Assuntos
Encefalomielite Autoimune Experimental , Ferroptose , Esclerose Múltipla , Animais , Encefalomielite Autoimune Experimental/genética , Ferroptose/genética , Regulação da Expressão Gênica , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Inflamação/genética , Camundongos , Neurônios/metabolismoRESUMO
In chronic inflammatory diseases of the central nervous system (CNS), immune cells persisting behind the blood-brain barrier are supposed to promulgate local tissue destruction. The drivers of such compartmentalized inflammation remain unclear, but tissue-resident memory T cells (TRM) represent a potentially important cellular player in this process. Here, we investigated whether resting CD8+ TRM persisting after cleared infection with attenuated lymphocytic choriomeningitis virus (LCMV) can initiate immune responses directed against cognate self-antigen in the CNS. We demonstrated that time-delayed conditional expression of the LCMV glycoprotein as neo-self-antigen by glia cells reactivated CD8+ TRM. Subsequently, CD8+ TRM expanded and initiated CNS inflammation and immunopathology in an organ-autonomous manner independently of circulating CD8+ T cells. However, in the absence of CD4+ T cells, TCF-1+ CD8+ TRM failed to expand and differentiate into terminal effectors. Similarly, in human demyelinating CNS autoimmune lesions, we found CD8+ T cells expressing TCF-1 that predominantly exhibited a TRM-like phenotype. Together, our study provides evidence for CD8+ TRM-driven CNS immunopathology and sheds light on why inflammatory processes may evade current immunomodulatory treatments in chronic autoimmune CNS conditions.