scholarly journals O7‐5: The role of increasing TIM3 on T cells in patients with nontuberculous mycobacterial lung disease: From immune cell dysfunction to clinical severity

Respirology ◽  
2021 ◽  
Vol 26 (S3) ◽  
pp. 21-22
Keyword(s):  
T Cells ◽  
Lung Disease ◽  
Immune Cell ◽  
Clinical Severity ◽  
Cell Dysfunction ◽  
Nontuberculous Mycobacterial Lung Disease

scholarly journals The Trend of TIM3 Expression on T Cells in Patients With Nontuberculous Mycobacterial Lung Disease: From Immune Cell Dysfunction to Clinical Severity

2021 ◽  
Vol 12 ◽  
Author(s):  
Ping-Huai Wang ◽  
Ming-Fang Wu ◽  
Chi-Yu Hsu ◽  
Sheng-Wei Pan ◽  
Chin-Chung Shu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lung Disease ◽  
Cd8 T Cells ◽  
Cell Apoptosis ◽  
Interleukin 2 ◽  
Clinical Severity ◽  
Cd4 Cells ◽  
Nontuberculous Mycobacterial Lung Disease ◽  
Tnf Α

BackgroundThe incidence of nontuberculous mycobacterial lung disease (NTM-LD) is increasing worldwide. Immune exhaustion has been reported in NTM-LD, but T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3), a co-inhibitory receptor on T cells, has been scarcely studied.MethodsPatients with NTM-LD and healthy controls were prospectively recruited from July 2014 to August 2019 at three tertiary referral centers in Taiwan. We examined TIM3 expression on the T cells from the participants using flow cytometry. TIM3 expression was analyzed for different disease statuses and after treatment. The apoptosis and cytokine profiles were analyzed according to the TIM3 expression.ResultsAmong enrolled subjects (47 patients and 46 controls), TIM3 on CD4+ cells (6.44% vs. 4.12%, p = 0.028) and CD8+ cells (18.47% vs. 9.13%, p = 0.003) were higher in NTM-LD patients than in the controls. The TIM3 level on CD4+ and CD8+ T cells was positively associated with T-cell apoptosis in the NTM-LD patients. In stimulating peripheral blood mononuclear cells using PMA plus ionomycin, a high TIM3 level on T cells correlated with low interleukin-2 and tumor necrosis factor-alpha (TNF-α) on CD4+ cells and interferon-gamma and TNF-α on CD8+ T cells. For clinical manifestation, low body mass index (BMI), positive sputum acid-fast smear, and high radiographic score correlated with high TIM3 expression on T cells. After NTM treatment, TIM3+ decreased significantly on CD4+ and CD8+ T cells.ConclusionsIn patients with NTM-LD, TIM3+ expression increased over CD4+ and CD8+ T cells and correlated with cell apoptosis and specific cytokine attenuation. Clinically, TIM3+ T cells increased in patients with low BMI, high disease extent, and high bacilli burden but decreased after treatment.

scholarly journals AB0026 DECREASE OF ANGIOGENIC T CELLS IN CONNECTIVE TISSUE DISEASE-ASSOCIATED INTERSTITIAL LUNG DISEASE

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1046.3-1047
Author(s):  
V. Pulito-Cueto ◽  
S. Remuzgo Martinez ◽  
F. Genre ◽  
B. Atienza-Mateo ◽  
V. M. Mora-Cuesta ◽  
...  
Keyword(s):  
T Cells ◽  
Interstitial Lung Disease ◽  
Connective Tissue ◽  
Lung Disease ◽  
Cell Subset ◽  
Vascular Damage ◽  
Type I ◽  
Research Support ◽  
Angiogenic T Cells

Background:Interstitial lung disease (ILD) is one of the most significant complications of connective tissue diseases (CTD), leading to an increase of the morbidity and mortality in patients with CTD [1]. A specific T cell subset termed angiogenic T cells (TAng), that promote endothelial repair and revascularization, have been involved in the pathogenesis of CTD [2-4]. However, to the best of our knowledge, no information regarding the role of TAng in CTD-ILD+ is available.Objectives:To study, for the first time, the potential role of TAng related to vascular damage in CTD-ILD+.Methods:Peripheral venous blood was collected from 40 patients with CTD-ILD+ and three comparative groups: 44 CTD-ILD- patients, 21 idiopathic pulmonary fibrosis (IPF) patients and 20 healthy controls (HC). All subjects were recruited from the Rheumatology and Pneumology departments of Hospital Universitario Marqués de Valdecilla, Santander, Spain. Quantification of TAng was performed by flow cytometry. TAng were considered as triple-positive for CD3, CD31 and CXCR4.Results:Patients with CTD-ILD+ exhibited a significantly lower TAng frequency than CTD-ILD- patients (p<0.001). Similar results were obtained when patients with CTD-ILD+ were compared with HC (p=0.004) although no difference was observed between CTD-ILD+ and IPF. In addition, a significant increase of TAng frequency was shown in patients with CTD-ILD- in relation to IPF patients (p<0.001), while no difference was observed between CTD-ILD- and HC.Conclusion:Our results reveal a decrease of TAng frequency related to vascular damage in CTD-ILD+. Furthermore, we disclose that the presence of ILD is associated with lower TAng frequency.References:[1]Expert Rev Clin Immunol 2018;14(1):69-82.[2]Circulation 2007;116(15):1671-82.[3]Ann Rheum Dis 2015 74(5):921-7.[4]PLoS One 2017;12(8):e0183102.Acknowledgements:Personal funds, VP-C: PREVAL18/01 (IDIVAL); SR-M: RD16/0012/0009 (ISCIII-ERDF); LL-G: INNVAL20/06 (IDIVAL); RP-F: START PROJECT (FOREUM); RL-M: Miguel Servet type I CP16/00033 (ISCIII-ESF).Disclosure of Interests:Verónica Pulito-Cueto: None declared, Sara Remuzgo Martinez: None declared, Fernanda Genre: None declared, Belén Atienza-Mateo: None declared, Victor Manuel Mora-Cuesta: None declared, David Iturbe-Fernández: None declared, Leticia Lera-Gómez: None declared, Raquel Pérez-Fernández: None declared, Pilar Alonso Lecue: None declared, Javier Rodriguez Carrio: None declared, Diana Prieto-Peña: None declared, Virginia Portilla: None declared, Ricardo Blanco Speakers bureau: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Consultant of: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Grant/research support from: Abbvie, MSD and Roche, Alfonso Corrales: None declared, Jose Manuel Cifrián-Martínez: None declared, Raquel López-Mejías: None declared, Miguel A González-Gay Speakers bureau: Pfizer, Abbvie, MSD, Grant/research support from: Pfizer, Abbvie, MSD

scholarly journals Acetate correlates with disability and immune response in multiple sclerosis

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e10220 ◽  
Author(s):  
Silvia Pérez-Pérez ◽  
María Inmaculada Domínguez-Mozo ◽  
Aitana Alonso-Gómez ◽  
Silvia Medina ◽  
Noelia Villarrubia ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Short Chain Fatty Acids ◽  
Liquid Chromatography Mass Spectrometry ◽  
Peripheral Blood Mononuclear ◽  
Healthy Donors ◽  
Disability Status

Background Gut microbiota has been related to multiple sclerosis (MS) etiopathogenesis. Short-chain fatty acids (SCFA) are compounds derived from microbial metabolism that have a role in gut-brain axis. Objectives To analyse SCFA levels in plasma of MS patients and healthy donors (HD), and the possible link between these levels and both clinical data and immune cell populations. Methods Ninety-five MS patients and 54 HD were recruited. Patients were selected according to their score in the Expanded Disability Status Scale (EDSS) (49 EDSS ≤ 1.5, 46 EDSS ≥ 5.0). SCFA were studied in plasma samples by liquid chromatography-mass spectrometry. Peripheral blood mononuclear cells were studied by flow cytometry. Gender, age, treatments, EDSS and Multiple Sclerosis Severity Score (MSSS) were evaluated at the recruitment. Results Plasma acetate levels were higher in patients than in HD (p = 0.003). Patients with EDSS ≥ 5.0 had higher acetate levels than those with EDSS≤ 1.5 (p = 0.029), and HD (p = 2.97e–4). Acetate levels correlated with EDSS (r = 0.387; p = 1.08e–4) and MSSS (r = 0.265; p = 0.011). In untreated MS patients, acetate levels correlated inversely with CD4+ naïve T cells (r =  − 0.550, p = 0.001) and directly with CD8+ IL-17+ cells (r = 0.557; p = 0.001). Conclusions Plasma acetate levels are higher in MS patients than in HD. In MS there exists a correlation between plasma acetate levels, EDSS and increased IL-17+ T cells. Future studies will elucidate the role of SCFA in the disease.

scholarly journals The Role of T Cells and Macrophages in Asthma Pathogenesis: A New Perspective on Mutual Crosstalk

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Xueyi Zhu ◽  
Jie Cui ◽  
La Yi ◽  
Jingjing Qin ◽  
Wuniqiemu Tulake ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Activation ◽  
Immune Cell ◽  
Immune Microenvironment ◽  
Innate And Adaptive Immunity ◽  
Immune Cell Activation ◽  
Inflammatory Signals ◽  
Macrophage Dysfunction ◽  
New Perspective

Asthma is associated with innate and adaptive immunity mediated by immune cells. T cell or macrophage dysfunction plays a particularly significant role in asthma pathogenesis. Furthermore, crosstalk between them continuously transmits proinflammatory or anti-inflammatory signals, causing the immune cell activation or repression in the immune response. Consequently, the imbalanced immune microenvironment is the major cause of the exacerbation of asthma. Here, we discuss the role of T cells, macrophages, and their interactions in asthma pathogenesis.

CD24-Siglec-G Interaction Plays an Important in Reducing Experimental Graft-Versus-Host Disease (GVHD)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 453-453
Author(s):  
Tomomi Toubai ◽  
Rebecca Evers ◽  
Yaping Sun ◽  
Isao Tawara ◽  
Chen Liu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Fusion Protein ◽  
Immune Activation ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Negative Regulator ◽  
Clinical Severity ◽  
Allogeneic Bmt

Abstract Abstract 453 The role of host antigen presenting cells (APCs) on negatively regulating GVHD is not well understood. Members of the sialic acid binding Ig–like lectin-G (Siglec-G) is an immunoreceptor tyrosine-based inhibitory motifs (ITIM) or ITIM-like regions in its intracellular domain that negatively regulates immune activation induced by non-infectious damage associated molecules (DAMPs). Following conditioning for allogeneic BMT, several DAMPs are released which stimulate host APCs and enhance GVHD. But the role of negative regulators of DAMP associated immune activation, such as Siglecs, in regulating allo-reactivity is not known. We therefore utilized well defined clinically relevant murine models of allogeneic BMT to test the hypothesis that deficiency of a negative regulator of responses to DAMPs in the hosts, namely Siglec-G, will increase GVHD. B6 wild type (WT) and Siglec-G−/− animals were lethally irradiated (13Gy) and transplanted on day 0 with 5×106 bone marrow and 3×106 splenic CD90+T cells from either syngeneic WT-B6 or MHC mismatched BALB/c donors. The Siglec-G−/− animals showed significantly worse survival than the allo-WT animals (p=0.0045). The increased mortality was associated with an increase in GVHD specific clinical severity (p<0.05), donor T cell expansion (p<0.03), and serum levels of pro-inflammatory cytokines (TNFα, IFN-γ, p<0.05) on day +7 after BMT. We next evaluated whether this was because of Siglec-G deficiency only on the radiosensitive host APCs. To this end we generated [B6àB6Ly5.2] and [Siglec-G−/−àB6Ly5.2] BM chimeras and utilized them as recipients following lethal radiation. They were injected with 5×106 BM and 3×106 CD90+ T cells from either syngeneic WT B6 or allogeneic BALB/c donors. The allogeneic [Siglec-G−/−àB6Ly5.2] animals demonstrated significantly worse survival than the [B6àB6Ly5.2] animals (p<0.0001). We determined the converse, i.e. analyzed the role of Siglec-G on radio-resistant host APCs by generating [B6Ly5.2àB6] and [B6Ly5.2àSiglec-G−/−] BM chimeras and utilized them as recipients. [B6Ly5.2àSiglec-G−/−] chimeras demonstrated similar survival as [B6Ly5.2àB6] chimeras. These data collectively demonstrate that Siglec-G expression only on the host radiosensitive APCs is critical for protection from GVHD. To confirm the role of increased DAMPs in causing greater mortality we tested whether the intensity of conditioning affects the serum level of DAMPs (HMGB1, proinflammatory cytokines) and found that significantly greater levels of DAMPs were observed in the mice that received 13Gy than 8 Gy. Furthermore, consistent with the increased levels of DAMPs, Siglec-G−/− animals showed higher GVHD only after 13Gy radiation but not after 8Gy conditioning. Because responses to non-infectious DAMPs are regulated by Siglec-G through its interaction with CD24 we next hypothesized that enhanced CD24-Siglec-G interaction would mitigate GVHD following myeloablative conditioning. We first characterized stimulation of allogeneic T cell responses by Siglec-G−/− APCs. We utilized CD24−/− and WT BALB/c T cells as responders in an MLR with B6 and Siglec-G−/−stimulators. We found that Siglec-G−/− APCs expanded the CD24−/− T cells more than WT-B6 APCs. We next tested in vivo whether enhanced CD24-Siglec-G interaction would mitigate GVHD. We utilized a novel CD24 fusion protein (day-1, 100mg/mouse) and found that it decreased GVHD mortality only in the WT but not in the Siglec-G−/− animals. Together our data demonstrate a critical role for CD24-Siglec-G interactions in regulating GVHD and suggest that administration of the novel CD24 fusion protein may be an innovative strategy to mitigate GVHD. Disclosures: No relevant conflicts of interest to declare.

scholarly journals T-Cell Dysfunction as a Limitation of Adoptive Immunotherapy: Current Concepts and Mitigation Strategies

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 598
Author(s):  
Valérie Janelle ◽  
Jean-Sébastien Delisle
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Ex Vivo ◽  
Genetically Engineered ◽  
Mitigation Strategies ◽  
Cellular Immunotherapy ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

Over the last decades, cellular immunotherapy has revealed its curative potential. However, inherent physiological characteristics of immune cells can limit the potency of this approach. Best defined in T cells, dysfunction associated with terminal differentiation, exhaustion, senescence, and activation-induced cell death, undermine adoptive cell therapies. In this review, we concentrate on how the multiple mechanisms that articulate the various forms of immune dysfunction impact cellular therapies primarily involving conventional T cells, but also other lymphoid subtypes. The repercussions of immune cell dysfunction across the full life cycle of cell therapy, from the source material, during manufacturing, and after adoptive transfer, are discussed, with an emphasis on strategies used during ex vivo manipulations to limit T-cell dysfunction. Applicable to cellular products prepared from native and unmodified immune cells, as well as genetically engineered therapeutics, the understanding and potential modulation of dysfunctional features are key to the development of improved cellular immunotherapies.

scholarly journals PD-1 blockade exacerbates Mycobacterium tuberculosis infection in rhesus macaques

2021 ◽  
Vol 6 (55) ◽  
pp. eabf3861
Author(s):  
Keith D. Kauffman ◽  
Shunsuke Sakai ◽  
Nickiana E. Lora ◽  
Sivaranjani Namasivayam ◽  
Paul J. Baker ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Cell Function ◽  
Immune Cell ◽  
Rhesus Macaques ◽  
Imaging Studies ◽  
Chronic Infections ◽  
Mycobacterium Tuberculosis Infection ◽  
Cell Responses

Boosting immune cell function by targeting the coinhibitory receptor PD-1 may have applications in the treatment of chronic infections. Here, we examine the role of PD-1 during Mycobacterium tuberculosis (Mtb) infection of rhesus macaques. Animals treated with anti–PD-1 monoclonal antibody developed worse disease and higher granuloma bacterial loads compared with isotype control–treated monkeys. PD-1 blockade increased the number and functionality of granuloma Mtb-specific CD8 T cells. In contrast, Mtb-specific CD4 T cells in anti–PD-1–treated macaques were not increased in number or function in granulomas, expressed increased levels of CTLA-4, and exhibited reduced intralesional trafficking in live imaging studies. In granulomas of anti–PD-1–treated animals, multiple proinflammatory cytokines were elevated, and more cytokines correlated with bacterial loads, leading to the identification of a role for caspase 1 in the exacerbation of tuberculosis after PD-1 blockade. Last, increased Mtb bacterial loads after PD-1 blockade were found to associate with the composition of the intestinal microbiota before infection in individual macaques. Therefore, PD-1–mediated coinhibition is required for control of Mtb infection in macaques, perhaps because of its role in dampening detrimental inflammation and allowing for normal CD4 T cell responses.

scholarly journals OP0136 RITUXIMAB PREVENTS THE PROGRESSION OF B-CELL DRIVEN INFLAMMATORY INFILTRATE IN THE MINOR SALIVARY GLANDS OF PRIMARY SJOGREN’S SYNDROME BY DOWNREGULATING IMMUNOLOGICAL PATHWAYS KEY IN ECTOPIC GERMINAL CENTRE ORGANIZATION: RESULTS FROM THE TRACTISS TRIAL

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 79-80
Author(s):  
E. Pontarini ◽  
F. Chowdhury ◽  
E. Sciacca ◽  
S. Grigoriadou ◽  
F. Rivellese ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Histological Analysis ◽  
Immune Cell ◽  
Salivary Flow ◽  
Memory B Cells ◽  
Cell Recruitment ◽  
Immune Cell Recruitment

Background:The pathogenic role of B-cells in primary Sjögren’s Syndrome (pSS) is well established and B cell abnormalities. Because of the substantial role of B-cells, rituximab (RTX), a chimeric anti-CD20 monoclonal antibody, has been considered as a potential biologic disease modifying drug to reduce disease activity in pSS. To date, the TRial for Anti-B-Cell Therapy In patients with pSS (TRACTISS) is the largest multi-centre, placebo-controlled trial with RTX. Despite the unmet primary endpoints (30% reduction in fatigue or oral dryness, measured by visual analogue scale), RTX treated patients showed an improvement in unstimulated whole salivary flow (Bowman et al. Arthritis Rheumatol 2017;69:1440–1450).Objectives:To provide the first longitudinal transcriptomic and histological analysis at 3 time points over 48 weeks of labial SGs of pSS patients treated with RTX, in comparison to placebo, from the TRACTISS cohort.Methods:26 pSS patients randomised to RTX or placebo arm consented for labial SG biopsies at baseline, weeks 16 and 48. Patients received two 1000mg cycles of RTX or placebo at baseline and week 24. SG focus score, inflammatory aggregate area fraction, B-cells (CD20+), T-cells (CD3+), follicular dendritic cells (FDCs) (CD21+) and plasma cells (CD138+) density were assessed by H&E and immunofluorescence staining. The histological analysis was performed by digital imaging using QuPath software. RNA was extracted from matched labial SG lobules and sequenced with Illumina platform. A Principal Component Analysis (PCA) and features driving the PCA were investigated along with the most influential gene loadings. The limma-voom R pipeline was used to extract Differential Expressed Genes (DEGs) between placebo and RTX group at week 48, and gene ontology (GO) enrichment analysis performed through EnrichR to derive GO terms and pathways associated with DEGs.Results:Placebo-treated labial SGs showed a worsening of inflammation highlighted by the increment of B-cell density, development of new FDC networks, and a higher ectopic GC prevalence at week 48, compared to RTX-treated patients. No difference in total T-cells and plasma cell infiltration was observed. RTX downregulated genes involved in immune cell recruitment and inflammatory aggregate organisation (e.g. CCR7, CCL19, CD52, and PDCD1) and gene signature-based analysis of 64 immune cell types highlighted how RTX preferentially blocked class-switched- and memory-B-cells infiltration in SGs at week 48. Pathway analyses confirmed the downregulation of leukocyte migration, MHC class II antigen presentation, and T-cell co-stimulation immunological pathways, such as the CD40 receptor complex pathway. The analysis of placebo SGs transcriptomic at week 48 showed a higher expression of genes linked to ectopic GC organisation, such as CXCL13, CCL19, LTβ, in female compared to male subjects. Gender was confirmed as a key co-variate responsible for most of the variation in the PCA, together with the SG focus score and the foci area fraction.Conclusion:Treatment with RTX showed beneficial effects on labial SG inflammatory infiltration in pSS, by downregulating genes involved in immune cell recruitment, activation and organisation in ectopic GCs. Class-switched-B-cells, memory-B-cells and FDC network development were primarily affected appearing to be responsible for the lack of progression in SG B cell infiltration in the RTX compared to the placebo arm in which clear worsening of SG immunopathology over 48 weeks was detected in female patients. Although a clear association with the clinical improvement in unstimulated salivary flow observed at week 48 in RTX-treated patients could not be established given the low number of patients consenting to 3 longitudinal biopsies it is conceivable that RTX is responsible for preserving exocrine function.Acknowledgements:SJB receives a salary contribution from the NIHR Birmingham Biomedical Research Centre.Disclosure of Interests:Elena Pontarini: None declared, Farzana Chowdhury: None declared, Elisabetta Sciacca: None declared, Sofia Grigoriadou: None declared, Felice Rivellese: None declared, Davide Lucchesi: None declared, Katriona Goldmann: None declared, Liliane Fossati-Jimack: None declared, Paul Emery: None declared, Wan Fai Ng: None declared, Nurhan Sutcliffe: None declared, Colin Everett: None declared, Catherine Fernandez: None declared, Anwar Tappuni: None declared, Myles Lewis: None declared, Costantino Pitzalis: None declared, Simon J. Bowman Consultant of: SJB In 2020 I have received consultancy fees from Novartis, Abbvie and Galapagos., Michele Bombardieri: None declared

scholarly journals The role of synovial T-cell infiltration following knee joint injury in symptoms and progression to osteoarthritis

2019 ◽  
Author(s):  
Babak Moradi ◽  
Miriam T Jackson ◽  
Cindy C. Shu ◽  
Susan M Smith ◽  
Margaret M Smith ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cell ◽  
Post Injury ◽  
Joint Injury ◽  
Cell Responses ◽  
Cellular Events ◽  
Bona Fide

AbstractObjectivesIdentification of osteoarthritis(OA)-specific synovial inflammatory pathways, and when in the clinical course they are active, is critical for their utility as therapeutic targets. We directly compared the mononuclear inflammatory/immune-cell responses following joint injury that does and does-not lead to OA, to define bona-fide OA-associated cellular events.MethodsWe undertook detailed temporal flow-cytometric and mRNA expression analysis in mice after sham or medial-meniscal-destiblization (DMM) surgery. We compared this with patients with meniscal injury and OA, and evaluated the role of synovial monocytes/macrophages versus lymphocytes in catabolic metalloproteinase secrection in vitro. We determined the effect of transient acute or delayed systemic T-cell depletion on DMM-induced OA pathology.ResultsOA-inducing/DMM and non-OA-inducing/Sham surgery had identical synovial monocyte/macrophage number, activation and polarization. The number and activation of synovial (not splenic or peripheral-blood) CD4 and CD8 lymphocytes was increased from 1-day after DMM versus Sham, and showed a persistent cyclical elevation throughout OA onset and progression. There was a temporal imbalance in synovial Th17/Treg and Th1/Th2 lymphocytes during DMM-induced OA initiation and progression. We confirmed early post-injury and late-OA CD3/CD8 T-cell responses in synovial tissues from patients, identified an association between CD8 and early post-injury symptoms, and defined a significant role for CD3+T-cells in synovial metalloproteinase secretion. Anti-CD3 cell-depletion studies in mice confirmed a key role for the earliest post-injury T-cell response in long-term OA pathology.ConclusionsWe identify a hitherto unappreciated pathophysiological role of acute T-cell activation after joint injury in long-term post-traumatic OA risk, providing a novel diagnostic and therapeutic target.Key MessagesWhat is already known about this subject?The presence of synovitis/joint-inflammation increases the risk not only of osteoarthritis (OA) progression but incident disease. While numerous inflammatory effectors including macrophages and lymphocytes have been identified in OA, their disease-specificity, temporal regulation, and association with risk of pathology onset and progression is lacking.How does this study add?By directly comparing the mononuclear inflammatory/immune-cell responses following significant joint injury that does (medial-meniscal-destabilization; DMM) and does-not (Sham-surgery) lead to OA in mice, we have defined bona-fide OA-associated cellular events. There was no difference in synovial or systemic monocyte/macrophage cell number, activation or polarization between DMM and Sham, both showing a successful wound-healing response. In contrast, increases in number and activation of synovial Th1- and Th17-CD4, and CD8 T-cells in DMM compared with Sham occurred within the first 3 days, and while recurring cyclically through subsequent disease onset, depletion studies indicated this initial influx was key to long-term ptOA risk.How might this impact on clinical practice of future developments?Acute increases in synovial T-cells following jont injury may be both a novel marker of OA risk, and a target to reduce long term structural damage.

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