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1. Conquest of the Cape, 1806

Author

Grainger, John R.

Subjects
SOUTH AFRICA (REPUBLIC) - History, MILITARY HISTORY - South Africa (Republic)
Abstract

bibliog

Published
1993

6. Retinoic acid controls the homeostasis of pre-cDC–derived splenic and intestinal dendritic cells

Author

Klebanoff, Christopher A, Spencer, Sean P, Torabi-Parizi, Parizad, Grainger, John R, Roychoudhuri, Rahul, Ji, Yun, Sukumar, Madhusudhanan, Muranski, Pawel, Scott, Christopher D, Hall, Jason A, Ferreyra, Gabriela A, Leonardi, Anthony J, Borman, Zachary A, Wang, Jinshan, Palmer, Douglas C, Wilhelm, Christoph, Cai, Rongman, Sun, Junfeng, Napoli, Joseph L, Danner, Robert L, Gattinoni, Luca, Belkaid, Yasmine, and Restifo, Nicholas P

Subjects
Vaccine Related, Nutrition, Prevention, Digestive Diseases, Biodefense, Emerging Infectious Diseases, 1.1 Normal biological development and functioning, Underpinning research, Inflammatory and immune system, Zero Hunger, Animals, Cell Differentiation, Cell Proliferation, Cell Survival, Dendritic Cells, Female, Histocompatibility Antigens Class II, Homeostasis, Humans, Immunophenotyping, Intestinal Mucosa, Intestines, Mice, Neoplasms, Organ Specificity, Phenotype, Receptors, Retinoic Acid, Signal Transduction, Spleen, Tretinoin, Vitamin A, Whole-Body Irradiation, Medical and Health Sciences, Immunology
Abstract

Dendritic cells (DCs) comprise distinct populations with specialized immune-regulatory functions. However, the environmental factors that determine the differentiation of these subsets remain poorly defined. Here, we report that retinoic acid (RA), a vitamin A derivative, controls the homeostasis of pre-DC (precursor of DC)-derived splenic CD11b(+)CD8α(-)Esam(high) DCs and the developmentally related CD11b(+)CD103(+) subset within the gut. Whereas mice deprived of RA signaling significantly lost both of these populations, neither pre-DC-derived CD11b(-)CD8α(+) and CD11b(-)CD103(+) nor monocyte-derived CD11b(+)CD8α(-)Esam(low) or CD11b(+)CD103(-) DC populations were deficient. In fate-tracking experiments, transfer of pre-DCs into RA-supplemented hosts resulted in near complete conversion of these cells into the CD11b(+)CD8α(-) subset, whereas transfer into vitamin A-deficient (VAD) hosts caused diversion to the CD11b(-)CD8α(+) lineage. As vitamin A is an essential nutrient, we evaluated retinoid levels in mice and humans after radiation-induced mucosal injury and found this conditioning led to an acute VAD state. Consequently, radiation led to a selective loss of both RA-dependent DC subsets and impaired class II-restricted auto and antitumor immunity that could be rescued by supplemental RA. These findings establish a critical role for RA in regulating the homeostasis of pre-DC-derived DC subsets and have implications for the management of patients with immune deficiencies resulting from malnutrition and irradiation.

Published
2013

7. CD163 and Tim-4 identify resident intestinal macrophages across sub-tissular regions that are spatially regulated by TGF-β

Author

Prise, Ian E, primary, Jayaraman, Vignesh, additional, Kästele, Verena, additional, Daw, Rufus H, additional, Wemyss, Kelly, additional, Bridgeman, Hayley, additional, Tamburrano, Sabrina, additional, Strangward, Patrick, additional, Chew, Christine, additional, Martens, Liesbet, additional, Scott, Charlotte L., additional, Guilliams, Martin, additional, Adamson, Antony D, additional, Konkel, Joanne E, additional, Shaw, Tovah N, additional, and Grainger, John R, additional

Published
2023
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9. The wild mouse bone marrow has a unique myeloid and lymphoid composition and phenotype

Author

Muir, Andrew, primary, Bennett, Alex, additional, Smith, Hannah, additional, Logunova, Larisa, additional, Wolfenden, Andrew, additional, Fenn, Jonathan, additional, Lowe, Ann E, additional, Brass, Andy, additional, Grainger, John R, additional, Konkel, Joanne E, additional, Bradley, Janette E, additional, Mair, Iris, additional, and Else, Kathryn J, additional

Published
2023
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10. Monocyte migration profiles define disease severity in acute COVID-19 and unique features of long COVID

Author

Scott, Nicholas A, Pearmain, Laurence, Knight, Sean B, Brand, Oliver, Morgan, David J, Jagger, Christopher, Harbach, Sarah, Khan, Saba, Shuwa, Halima A, Franklin, Miriam, Kästele, Verena, Williams, Thomas, Prise, Ian, McClure, Flora A, Hackney, Pamela, Smith, Lara, Menon, Madhvi, Konkel, Joanne E, Lawless, Criag, Wilson, James, Mathioudakis, Aleaxander G, Stanel, Stefan C, Ustianowski, Andrew, Lindergard, Gabriella, Brij, Seema, Diar Bakerly, Nawar, Dark, Paul, Brightling, Christopher, Rivera-Ortega, Pilar, Lord, Graham M, Horsley, Alex, Piper Hanley, Karen, Felton, Timothy, Simpson, Angela, Grainger, John R, Hussell, Tracy, and Mann, Elizabeth R

Subjects
Pulmonary and Respiratory Medicine, Chemokines, CXC/metabolism, Receptors, Scavenger/metabolism, Patient Acuity, COVID-19, Convalescence, Chemokine CXCL16, Lung Injury, Receptors, Chemokine/metabolism, Ligands, Post-Acute COVID-19 Syndrome, Monocytes/metabolism, Influenza, Human, Receptors, Virus/metabolism, Humans, Receptors, CXCR6
Abstract

BackgroundCOVID-19 is associated with a dysregulated immune response but it is unclear how immune dysfunction contributes to the chronic morbidity persisting in many COVID-19 patients during convalescence (long COVID).MethodsWe assessed phenotypical and functional changes of monocytes in COVID-19 patients during hospitalisation and up to 9 months of convalescence following COVID-19, respiratory syncytial virus or influenza A. Patients with progressive fibrosing interstitial lung disease were included as a positive control for severe, ongoing lung injury.ResultsMonocyte alterations in acute COVID-19 patients included aberrant expression of leukocyte migration molecules, continuing into convalescence (n=142) and corresponding with specific symptoms of long COVID. Long COVID patients with unresolved lung injury, indicated by sustained shortness of breath and abnormal chest radiology, were defined by high monocyte expression of C-X-C motif chemokine receptor 6 (CXCR6) (pConclusionsOur data define unique monocyte signatures that define subgroups of long COVID patients, indicating a key role for monocyte migration in COVID-19 pathophysiology. Targeting these pathways may provide novel therapeutic opportunities in COVID-19 patients with persistent morbidity.

Published
2023

18. COVID-19 therapeutics: Challenges and directions for the future

Author

Robinson, Philip C., primary, Liew, David F. L., additional, Tanner, Helen L., additional, Grainger, John R., additional, Dwek, Raymond A., additional, Reisler, Ronald B., additional, Steinman, Lawrence, additional, Feldmann, Marc, additional, Ho, Ling-Pei, additional, Hussell, Tracy, additional, Moss, Paul, additional, Richards, Duncan, additional, and Zitzmann, Nicole, additional

Published
2022
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21. Integrated miRNA/cytokine/chemokine profiling reveals severity-associated step changes and principal correlates of fatality in COVID-19

Author

Wilson, Julie C., primary, Kealy, David, additional, James, Sally R., additional, Plowman, Tobias, additional, Newling, Katherine, additional, Jagger, Christopher, additional, Filbey, Kara, additional, Mann, Elizabeth R., additional, Konkel, Joanne E., additional, Menon, Madhvi, additional, Knight, Sean B., additional, Simpson, Angela, additional, Prihartadi, Aliya, additional, Forshaw, Greg, additional, Todd, Neil, additional, Yates, David R.A., additional, Grainger, John R., additional, Hussell, Tracy, additional, Kaye, Paul M., additional, Signoret, Nathalie, additional, and Lagos, Dimitris, additional

Published
2022
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23. Alterations in T and B cell function persist in convalescent COVID-19 patients

Author

Ahmed, Rohan, Avery, Miriam, Birchall, Katharine, Charsley, Evelyn, Chenery, Alistair, Chew, Christine, Clark, Richard, Connolly, Emma, Connolly, Karen, Dawson, Simon, Durrans, Laura, Durrington, Hannah, Egan, Jasmine, Filbey, Kara, Fox, Claire, Francis, Helen, Franklin, Miriam, Glasgow, Susannah, Godfrey, Nicola, Gray, Kathryn J., Grundy, Seamus, Guerin, Jacinta, Hackney, Pamela, Hayes, Chantelle, Hardy, Emma, Harris, Jade, John, Anu, Jolly, Bethany, Kästele, Verena, Kerry, Gina, Lui, Sylvia, Lin, Lijing, Mathioudakis, Alex G., Mitchell, Joanne, Moizer, Clare, Moore, Katrina, Moss, Stuart, Baker, Syed Murtuza, Oliver, Rob, Padden, Grace, Parkinson, Christina, Phuycharoen, Michael, Saha, Ananya, Salcman, Barbora, Scott, Nicholas A., Sharma, Seema, Shaw, Jane, Shaw, Joanne, Shepley, Elizabeth, Smith, Lara, Stephan, Simon, Stephens, Ruth, Tavernier, Gael, Tudge, Rhys, Wareing, Louis, Warren, Roanna, Williams, Thomas, Willmore, Lisa, Younas, Mehwish, Shuwa, Halima A., Shaw, Tovah N., Knight, Sean B., Wemyss, Kelly, McClure, Flora A., Pearmain, Laurence, Prise, Ian, Jagger, Christopher, Morgan, David J., Khan, Saba, Brand, Oliver, Mann, Elizabeth R., Ustianowski, Andrew, Bakerly, Nawar Diar, Dark, Paul, Brightling, Christopher E., Brij, Seema, Felton, Timothy, Simpson, Angela, Grainger, John R., Hussell, Tracy, Konkel, Joanne E., and Menon, Madhvi

Published
2021
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25. Inflammatory monocytes regulate pathologic responses to commensals during acute gastrointestinal infection

Author

Grainger, John R., Wohlfert, Elizabeth A., Fuss, Ivan J., Bouladoux, Nicolas, Askenase, Michael H., Legrand, Fanny, Koo, Lily Y., Brenchley, Jason M., Fraser, Iain D. C., and Belkaid, Yasmine

Subjects
Microbiota (Symbiotic organisms) -- Physiological aspects -- Genetic aspects -- Research, Immune response -- Physiological aspects -- Genetic aspects -- Research, Gastrointestinal diseases -- Health aspects -- Development and progression -- Genetic aspects -- Research, Biological sciences, Health
Abstract

The commensal flora can promote both immunity to pathogens and mucosal inflammation. How commensal-driven inflammation is regulated in the context of infection remains poorly understood. Here, we show that during [...]

Published
2013
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26. Alterations in T and B cell function persist in convalescent COVID-19 patients

Author

Shuwa, Halima A., primary, Shaw, Tovah N., additional, Knight, Sean B., additional, Wemyss, Kelly, additional, McClure, Flora A., additional, Pearmain, Laurence, additional, Prise, Ian, additional, Jagger, Christopher, additional, Morgan, David J., additional, Khan, Saba, additional, Brand, Oliver, additional, Mann, Elizabeth R., additional, Ustianowski, Andrew, additional, Bakerly, Nawar Diar, additional, Dark, Paul, additional, Brightling, Christopher E., additional, Brij, Seema, additional, Felton, Timothy, additional, Simpson, Angela, additional, Grainger, John R., additional, Hussell, Tracy, additional, Konkel, Joanne E., additional, Menon, Madhvi, additional, Ahmed, Rohan, additional, Avery, Miriam, additional, Birchall, Katharine, additional, Charsley, Evelyn, additional, Chenery, Alistair, additional, Chew, Christine, additional, Clark, Richard, additional, Connolly, Emma, additional, Connolly, Karen, additional, Dawson, Simon, additional, Durrans, Laura, additional, Durrington, Hannah, additional, Egan, Jasmine, additional, Filbey, Kara, additional, Fox, Claire, additional, Francis, Helen, additional, Franklin, Miriam, additional, Glasgow, Susannah, additional, Godfrey, Nicola, additional, Gray, Kathryn J., additional, Grundy, Seamus, additional, Guerin, Jacinta, additional, Hackney, Pamela, additional, Hayes, Chantelle, additional, Hardy, Emma, additional, Harris, Jade, additional, John, Anu, additional, Jolly, Bethany, additional, Kästele, Verena, additional, Kerry, Gina, additional, Lui, Sylvia, additional, Lin, Lijing, additional, Mathioudakis, Alex G., additional, Mitchell, Joanne, additional, Moizer, Clare, additional, Moore, Katrina, additional, Moss, Stuart, additional, Baker, Syed Murtuza, additional, Oliver, Rob, additional, Padden, Grace, additional, Parkinson, Christina, additional, Phuycharoen, Michael, additional, Saha, Ananya, additional, Salcman, Barbora, additional, Scott, Nicholas A., additional, Sharma, Seema, additional, Shaw, Jane, additional, Shaw, Joanne, additional, Shepley, Elizabeth, additional, Smith, Lara, additional, Stephan, Simon, additional, Stephens, Ruth, additional, Tavernier, Gael, additional, Tudge, Rhys, additional, Wareing, Louis, additional, Warren, Roanna, additional, Williams, Thomas, additional, Willmore, Lisa, additional, and Younas, Mehwish, additional

Published
2021
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28. GATA3 controls Foxp3+ regulatory T cell fate during inflammation in mice

Author

Wohlfert, Elizabeth A., Grainger, John R., Bouladoux, Nicolas, Konkel, Joanne E., Oldenhove, Guillaume, Ribeiro, Carolina Hager, Hall, Jason A., Yagi, Ryoji, Naik, Shruti, Bhairavabhotla, Ravikiran, Paul, William E., Bosselut, Remy, Wei, Gang, Zhao, Keji, Oukka, Mohamed, Zhu, Jinfang, and Belkaid, Yasmine

Subjects
Cytokines -- Properties, T cells -- Genetic aspects, Gene expression -- Research, Genetic regulation -- Research, Health care industry
Abstract

Tregs not only keep immune responses to autoantigens in check, but also restrain those directed toward pathogens and the commensal microbiota. Control of peripheral immune homeostasis by Tregs relies on [...]

Published
2011
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29. Generation of pathogenic [T.sub.H]17 cells in the absence of TGF-β signalling

Author

Ghoreschi, Kamran, Laurence, Arian, Yang, Xiang-Ping, Tato, Cristina M., McGeachy, Mandy J., Konkel, Joanne E., Ramos, Haydee L., Wei, Lai, Davidson, Todd S., Bouladoux, Nicolas, Grainger, John R., Chen, Qian, Kanno, Yuka, Watford, Wendy T., Sun, Hong-Wei, Eberl, Gerard, Shevach, Ethan M., Belkaid, Yasmine, Cua, Daniel J., Chen, WanJun, and O'Shea, John J.

Subjects
Autoimmunity -- Health aspects -- Research -- Physiological aspects, CD4 lymphocytes -- Physiological aspects -- Genetic aspects -- Research -- Health aspects, Transforming growth factors -- Physiological aspects -- Genetic aspects -- Research -- Health aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

[CD4.sup.+] T-helper cells that selectively produce interleukin (IL)-17 ([T.sub.H]17), are critical for host defence and autoimmunity (1-4). Although crucial for [T.sub.H]17 cells in vivo (5,6), IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-[β.sub.1] have been proposed to be the factors responsible for initiating specification (7-10). Here we show that [T.sub.H]17 differentiation can occur in the absence of TGF-β signalling. Neither IL-6 nor IL-23 alone efficiently generated [T.sub.H]17 cells; however, these cytokines in combination with IL-1β effectively induced IL-17 production in naive precursors, independently of TGF-β. Epigenetic modification of the Il17a, Il17f and Rorc promoters proceeded without TGF-β1, allowing the generation of cells that co-expressed RORγt (encoded by Rorc) and T-bet. [T-bet.sup.+] RORy[t.sup.+] [T.sub.H]17 cells are generated in vivo during experimental allergic encephalomyelitis, and adoptively transferred [T.sub.H]17 cells generated with IL-23 without TGF-β1 were pathogenic in this disease model. These data indicate an alternative mode for [T.sub.H]17 differentiation. Consistent with genetic data linking IL23R with autoimmunity, our findings re-emphasize the importance of IL-23 and therefore may have therapeutic implications., TGF-βl is important for murine [T.sub.H]17 differentiation (7,8) and accordingly, transgenic expression of a mutant TGF-β subunit receptor II (CD4dnTGF-βRII) in T cells interferes with the generation of [T.sub.H]17 cells [...]

Published
2010
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32. Longitudinal immune profiling reveals distinct features of COVID-19 pathogenesis

Author

Mann, Elizabeth R., Menon, Madhvi, Knight, Sean Blandin, Konkel, Joanne E., Jagger, Christopher, Shaw, Tovah N., Krishnan, Siddharth, Rattray, Magnus, Ustianowski, Andrew, Bakerly, Nawar Diar, Dark, Paul, Lord, Graham, Simpson, Angela, Felton, Timothy, Ho, Ling Pei, Feldmann, Marc, Grainger, John R., Hussell, Tracy, Ahmed, Rohan, Shuwa, Halima Ali, Avery, Miriam, Birchall, Katharine, Brand, Oliver, Charsley, Evelyn, Chenery, Alistair, Chew, Christine, Clark, Richard, Connolly, Emma, Connolly, Karen, Dawson, Simon, Durrans, Laura, Durrington, Hannah, Egan, Jasmine, Fox, Claire, Francis, Helen, Franklin, Miriam, Glasgow, Susannah, Godfrey, Nicola, Gray, Kathryn J., Grundy, Seamus, Guerin, Jacinta, Hackney, Pamela, Iqbal, Mudassar, Hayes, Chantelle, Hardy, Emma, Harris, Jade, John, Anu, Jolly, Bethany, Kästele, Verena, Khan, Saba, Lindergard, Gabriella, Lui, Sylvia, Lowe, Lesley, Mathioudakis, Alex G., McClure, Flora A., Mitchell, Joanne, Moizer, Clare, Moore, Katrina, Morgan, David, Moss, Stuart, Baker, Syed Murtuza, Oliver, Rob, Padden, Grace, Parkinson, Christina, Pearmain, Laurence, Phuychareon, Mike, Saha, Ananya, Salcman, Barbora, Scott, Nicholas A., Sharma, Seema, Shaw, Jane, Shaw, Joanne, Shepley, Elizabeth, Smith, Lara, Stephan, Simon, Stephens, Ruth, Tavernier, Gael, Tudge, Rhys, Wareing, Louis, Warren, Roanna, Williams, Thomas, Willmore, Lisa, Younas, Mehwish, Horsley, Alex, Harrison, Tim, Porter, Joanna, Djukanovic, Ratko, Marciniak, Stefan, Brightling, Chris, McGarvey, Lorcan, and Davies, Jane

Subjects
business.industry, T cell, Inflammation, Context (language use), Disease, Clinical trial, Pathogenesis, Immune system, medicine.anatomical_structure, Intensive care, Immunology, medicine, medicine.symptom, business
Abstract

BackgroundThe pathogenesis of COVID-19, caused by a novel strain of coronavirus (SARS-CoV-2), involves a complex host-virus interaction and is characterised by an exaggerated immune response, the specific components of which are poorly understood. Here we report the outcome of a longitudinal immune profiling study in hospitalised patients during the peak of the COVID-19 pandemic in the UK and show the relationship between immune responses and severity of the clinical presentation.MethodsThe Coronavirus Immune Response and Clinical Outcomes (CIRCO) study was conducted at four hospitals in Greater Manchester. Patients with SARS-CoV-2 infection, recruited as close to admission as possible, provided peripheral blood samples at enrolment and sequentially thereafter. Fresh samples were assessed for immune cells and proteins in whole blood and serum. Some samples were also stimulated for 3 hours with LPS and analysed for intracellular proteins. Results were stratified based on patient-level data including severity of symptoms and date of reported symptom onset.FindingsLongitudinal analysis showed a very high neutrophil to T cell ratio and abnormal activation of monocytes in the blood, which displayed high levels of the cell cycle marker, Ki67 and low COX-2. These properties all reverted in patient with good outcome. Unexpectedly, multiple aspects of inflammation were diminished as patients progressed in severity and time, even in ITU patients not recovering.InterpretationThis is the first detailed longitudinal analysis of COVID-19 patients of varying severity and outcome, revealing common features and aspects that track with severity. Patients destined for a severe outcome can be identified at admission when still displaying mild-moderate symptoms. We provide clues concerning pathogenesis that should influence clinical trials and therapeutics. Targeting pathways involved in neutrophil and monocyte release from the bone marrow should be tested in patients with COVID-19.FundingThe Kennedy Trust for Rheumatology Research, The Wellcome Trust, The Royal Society, The BBSRC, National Institute for Health Research (NIHR) Biomedical Research Centres (BRC).Research in contextEvidence before this studyAnalysis of the literature before the study via pubmed and bioRxiv searches using the terms COVID-19, SARS-CoV2, immune and inflammation (with the last search performed on 27th April 2020) showed evidence of an overactive immune response in a handful of studies in cross-sectional analyses all done at a single time point.Added value of this studyTo determine the role of the immune response in a disease process, it is necessary to correlate immune activity with clinical parameters dynamically. In this study patients presented to hospital at different stages of disease so we took samples at different time-points to provide an accurate picture of the relevant pathobiology. In order to avoid loss of large components of the immune system due to the processes of storage, longitudinal samples were interrogated in real time to reveal the full immune alterations in COVID-19.Implications of all the available evidenceRespiratory viruses continue to cause devastating global disease. The finding of altered myelopoiesis, with excess neutrophils and altered monocyte function, as dominant features in our study provides an incentive for clinical testing of therapeutics that specifically target this pathobiology. Given that inflammation is greatest prior to admission to intensive care, trials of specific immune-modulating therapies should be considered earlier in admission. Future studies of COVID-19 mechanisms should place more emphasis on longitudinal analyses since disease changes dramatically over time.

Published
2020

34. Integrated miRNA/Cytokine/Chemokine Profiling Reveals Severity-Associated Step Changes and Principal Correlates of Fatality in COVID-19

Author

Wilson, Julie, primary, Kealy, David, additional, James, Sally R., additional, Plowman, Tobias, additional, Newling, Katherine, additional, Jagger, Christopher, additional, Filbey, Kara J., additional, Mann, Elizabeth R., additional, Konkel, Joanne E., additional, Menon, Madhvi, additional, Knight, Sean B., additional, Simpson, Angela, additional, Group, CIRCO Collaborative, additional, Prihartadi, Aliya, additional, Forshaw, Greg, additional, Todd, Neil, additional, Yates, David R.A., additional, Grainger, John R., additional, Hussell, Tracy, additional, Kaye, Paul M., additional, Signoret, Nathalie, additional, and Lagos, Dimitris, additional

Published
2021
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35. Minimal Differentiation of Classical Monocytes as They Survey Steady-State Tissues and Transport Antigen to Lymph Nodes

Author

Jakubzick, Claudia, Gautier, Emmanuel L., Gibbings, Sophie L., Sojka, Dorothy K., Schlitzer, Andreas, Johnson, Theodore E., Ivanov, Stoyan, Duan, Qiaonan, Bala, Shashi, Condon, Tracy, van Rooijen, Nico, Grainger, John R., Belkaid, Yasmine, Maʼayan, Avi, Riches, David W.H., Yokoyama, Wayne M., Ginhoux, Florent, Henson, Peter M., and Randolph, Gwendalyn J.

Published
2013
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41. Long-Lasting Alterations in T and B Cell Function in Convalescent COVID-19 Patients

Author

Shuwa, Halima Ali, primary, Shaw, Tovah N., additional, Knight, S. B., additional, McClure, Flora A., additional, Wemyss, Kelly, additional, Prise, Ian, additional, Permain, Laurence, additional, Jagger, Christopher, additional, Morgan, D. J., additional, Khan, S., additional, Brand, O., additional, Mann, E. R., additional, Ustianowski, Andrew, additional, Diar Bakerly, Nawar, additional, Dark, Paul, additional, Brightling, Christopher, additional, Brij, Seema, additional, Study, CIRCO, additional, Felton, T., additional, Simpson, A., additional, Grainger, John R., additional, Hussell, Tracy, additional, Konkel, Joanne E., additional, and Menon, Madhvi, additional

Published
2020
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43. Th17-to-Tfh plasticity during periodontitis limits disease pathology

Author

McClure, Flora A., Wemyss, Kelly, Cox, Joshua R., Bridgeman, Hayley M., Prise, Ian E., King, James I., Jaigirdar, Shafqat, Whelan, Annie, Jones, Gareth W., Grainger, John R., Hepworth, Matthew R., and Konkel, Joanne E.

Abstract

Th17 cell plasticity is crucial for development of autoinflammatory disease pathology. Periodontitis is a prevalent inflammatory disease where Th17 cells mediate key pathological roles, yet whether they exhibit any functional plasticity remains unexplored. We found that during periodontitis, gingival IL-17 fate-mapped T cells still predominantly produce IL-17A, with little diversification of cytokine production. However, plasticity of IL-17 fate-mapped cells did occur during periodontitis, but in the gingiva draining lymph node. Here, some Th17 cells acquired features of Tfh cells, a functional plasticity that was dependent on IL-6. Notably, Th17-to-Tfh diversification was important to limit periodontitis pathology. Preventing Th17-to-Tfh plasticity resulted in elevated periodontal bone loss that was not simply due to increased proportions of conventional Th17 cells. Instead, loss of Th17-to-Tfh cells resulted in reduced IgG levels within the oral cavity and a failure to restrict the biomass of the oral commensal community. Thus, our data identify a novel protective function for a subset of otherwise pathogenic Th17 cells during periodontitis.

Published
2024
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44. Longitudinal immune profiling reveals key myeloid signatures associated with COVID-19.

Author

Mann, Elizabeth R., Menon, Madhvi, Knight, Sean Blandin, Konkel, Joanne E., Jagger, Christopher, Shaw, Tovah N., Krishnan, Siddharth, Rattray, Magnus, Ustianowski, Andrew, Bakerly, Nawar Diar, Dark, Paul, Lord, Graham M., Simpson, Angela, Felton, Timothy, Ho, Ling-Pei, Feldmann, Marc, Grainger, John R., and Hussell, Tracy

Abstract

Myeloid upheaval in severe COVID-19: Severe COVID-19 disease is associated with immune hyperactivation accompanied by "cytokine storm." Mann et al. used longitudinal analysis of fresh blood samples from hospitalized COVID-19 patients to search for biomarkers that signal impending progression to severe disease. Several phenotypic and functional abnormalities of CD14+ blood monocytes emerged as early-stage biomarkers predictive of increased severity of disease. Monocytes from patients with severe COVID-19 activated in vitro with lipopolysaccharide displayed increased proliferation and decreased expression of the prostaglandin-synthesizing cyclooxygenase-2 (COX-2) enzyme. Premature release of immature myeloid cells from the bone marrow contributes to innate immune dysfunction, causing more extensive lung damage and poorer clinical outcomes. These findings suggest that early treatment of COVID-19 targeting emergency myelopoiesis may help reduce the risk of subsequent clinical deterioration. COVID-19 pathogenesis is associated with an exaggerated immune response. However, the specific cellular mediators and inflammatory components driving diverse clinical disease outcomes remain poorly understood. We undertook longitudinal immune profiling on both whole blood and peripheral blood mononuclear cells of hospitalized patients during the peak of the COVID-19 pandemic in the United Kingdom. Here, we report key immune signatures present shortly after hospital admission that were associated with the severity of COVID-19. Immune signatures were related to shifts in neutrophil to T cell ratio, elevated serum IL-6, MCP-1, and IP-10 and modulation of CD14+ monocyte phenotype and function. Modified features of CD14+ monocytes included poor induction of the prostaglandin-producing enzyme, COX-2, and enhanced expression of the cell cycle marker Ki-67. Longitudinal analysis revealed reversion of some immune features back to the healthy median level in patients with a good eventual outcome. These findings identify previously unappreciated alterations in the innate immune compartment of patients with COVID-19 and lend support to the idea that therapeutic strategies targeting release of myeloid cells from bone marrow should be considered in this disease. Moreover, they demonstrate that features of an exaggerated immune response are present early after hospital admission, suggesting that immunomodulating therapies would be most beneficial at early time points. [ABSTRACT FROM AUTHOR]

Published
2020
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45. Tissue-resident macrophages in the intestine are long lived and defined by Tim-4 and CD4 expression

Author

Shaw, Tovah N., primary, Houston, Stephanie A., additional, Wemyss, Kelly, additional, Bridgeman, Hayley M., additional, Barbera, Thomas A., additional, Zangerle-Murray, Tamsin, additional, Strangward, Patrick, additional, Ridley, Amanda J.L., additional, Wang, Ping, additional, Tamoutounour, Samira, additional, Allen, Judith E., additional, Konkel, Joanne E., additional, and Grainger, John R., additional

Published
2018
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46. A dominant role for the methyl-CpG-binding protein Mbd2 in controlling Th2 induction by dendritic cells

Author

Cook, Peter C., Owen, Heather, Deaton, Aimée M., Borger, Jessica G., Brown, Sheila L., Clouaire, Thomas, Jones, Gareth-Rhys, Jones, Lucy H., Lundie, Rachel J., Marley, Angela K., Morrison, Vicky L., Phythian-Adams, Alexander T., Wachter, Elisabeth, Webb, Lauren M., Sutherland, Tara E., Thomas, Graham D., Grainger, John R., Selfridge, Jim, McKenzie, Andrew N. J., Allen, Judith E., Fagerholm, Susanna C., Maizels, Rick M., Ivens, Alasdair C., Bird, Adrian, and MacDonald, Andrew S.

Subjects
CD4-Positive T-Lymphocytes, Chromatin Immunoprecipitation, Chemistry(all), Enzyme-Linked Immunosorbent Assay, Physics and Astronomy(all), Lymphocyte Activation, Article, Epigenesis, Genetic, Mice, Th2 Cells, Hypersensitivity, Animals, RNA, Messenger, Mice, Knockout, Biochemistry, Genetics and Molecular Biology(all), Reverse Transcriptase Polymerase Chain Reaction, Pyroglyphidae, Cell Polarity, Dendritic Cells, Schistosoma mansoni, Allergens, DNA Methylation, Flow Cytometry, Schistosomiasis mansoni, DNA-Binding Proteins, Gene Expression Regulation
Abstract

Dendritic cells (DCs) direct CD4+ T-cell differentiation into diverse helper (Th) subsets that are required for protection against varied infections. However, the mechanisms used by DCs to promote Th2 responses, which are important both for immunity to helminth infection and in allergic disease, are currently poorly understood. We demonstrate a key role for the protein methyl-CpG-binding domain-2 (Mbd2), which links DNA methylation to repressive chromatin structure, in regulating expression of a range of genes that are associated with optimal DC activation and function. In the absence of Mbd2, DCs display reduced phenotypic activation and a markedly impaired capacity to initiate Th2 immunity against helminths or allergens. These data identify an epigenetic mechanism that is central to the activation of CD4+ T-cell responses by DCs, particularly in Th2 settings, and reveal methyl-CpG-binding proteins and the genes under their control as possible therapeutic targets for type-2 inflammation., How anti-helminth and allergic immune responses are initiated is poorly understood. Here the authors show that to trigger these responses, dendritic cells specifically require methyl-CpG-binding domain-2, a protein promoting repressed chromatin state.

Published
2015

47. Cultivation of Heligmosomoides Polygyrus: An Immunomodulatory Nematode Parasite and its Secreted Products

Author

Johnston, Chris J.C., Robertson, Elaine, Harcus, Yvonne, Grainger, John R., Coakley, Gillian, Smyth, Danielle J., McSorley, Henry J., and Maizels, Rick

Subjects
Mouse, Excretory-Secretory Products, Life cycle, Neuroscience(all), Immunology, Heligmosomoides polygyrus, Mice, Immunology and Microbiology(all), parasitic diseases, Helminth, Animals, Excretory-Secretory products, Issue 98, Life Cycle, Life Cycle Stages, Nematospiroides dubius, Biochemistry, Genetics and Molecular Biology(all), Mice, Inbred C57BL, Chemical Engineering(all), Mice, Inbred CBA, Infection
Abstract

Heligmosomoides polygyrus (formerly known as Nematospiroides dubius, and also referred to by some as H. bakeri) is a gastrointestinal\ud helminth that employs multiple immunomodulatory mechanisms to establish chronic infection in mice and closely resembles prevalent human\ud helminth infections. H. polygyrus has been studied extensively in the field of helminth-derived immune regulation and has been found to potently\ud suppress experimental models of allergy and autoimmunity (both with active infection and isolated secreted products). The protocol described in\ud this paper outlines management of the H. polygyrus life cycle for consistent production of L3 larvae, recovery of adult parasites, and collection of\ud their excretory-secretory products (HES).

Published
2015

48. A dominant role for the methyl-CpG-binding protein Mbd2 in controlling Th2 induction by dendritic cells

Author

Cook, Peter C, Owen, Heather, Deaton, Aimée M, Borger, Jessica G, Brown, Sheila L, Clouaire, Thomas, Jones, Gareth-Rhys, Jones, Lucy H, Lundie, Rachel J, Marley, Angela K, Morrison, Vicky L, Phythian-Adams, Alexander T, Wachter, Elisabeth, Webb, Lauren M, Sutherland, Tara E, Thomas, Graham D, Grainger, John R, Selfridge, Jim, McKenzie, Andrew N J, Allen, Judith E, Fagerholm, Susanna C, Maizels, Rick M, Ivens, Alasdair C, Bird, Adrian, MacDonald, Andrew S, Cook, Peter C, Owen, Heather, Deaton, Aimée M, Borger, Jessica G, Brown, Sheila L, Clouaire, Thomas, Jones, Gareth-Rhys, Jones, Lucy H, Lundie, Rachel J, Marley, Angela K, Morrison, Vicky L, Phythian-Adams, Alexander T, Wachter, Elisabeth, Webb, Lauren M, Sutherland, Tara E, Thomas, Graham D, Grainger, John R, Selfridge, Jim, McKenzie, Andrew N J, Allen, Judith E, Fagerholm, Susanna C, Maizels, Rick M, Ivens, Alasdair C, Bird, Adrian, and MacDonald, Andrew S

Abstract

Dendritic cells (DCs) direct CD4(+) T-cell differentiation into diverse helper (Th) subsets that are required for protection against varied infections. However, the mechanisms used by DCs to promote Th2 responses, which are important both for immunity to helminth infection and in allergic disease, are currently poorly understood. We demonstrate a key role for the protein methyl-CpG-binding domain-2 (Mbd2), which links DNA methylation to repressive chromatin structure, in regulating expression of a range of genes that are associated with optimal DC activation and function. In the absence of Mbd2, DCs display reduced phenotypic activation and a markedly impaired capacity to initiate Th2 immunity against helminths or allergens. These data identify an epigenetic mechanism that is central to the activation of CD4(+) T-cell responses by DCs, particularly in Th2 settings, and reveal methyl-CpG-binding proteins and the genes under their control as possible therapeutic targets for type-2 inflammation.

Published
2015

49. GATA3 controls Foxp3⁺ regulatory T cell fate during inflammation in mice.

Author

Wohlfert, Elizabeth A, Grainger, John R, Bouladoux, Nicolas, Konkel, Joanne JE, Oldenhove, Guillaume, Ribeiro, Carolina Hager, Hall, Jason A., Yagi, Ryoji, Naik, Shruti, Bhairavabhotla, Ravikiran, Paul, William, Bosselut, Remy, Wei, Gang, Zhao, Keji, Oukka, Mohamed, Zhu, Jinfang, Belkaid, Yasmine, Wohlfert, Elizabeth A, Grainger, John R, Bouladoux, Nicolas, Konkel, Joanne JE, Oldenhove, Guillaume, Ribeiro, Carolina Hager, Hall, Jason A., Yagi, Ryoji, Naik, Shruti, Bhairavabhotla, Ravikiran, Paul, William, Bosselut, Remy, Wei, Gang, Zhao, Keji, Oukka, Mohamed, Zhu, Jinfang, and Belkaid, Yasmine

Abstract

Tregs not only keep immune responses to autoantigens in check, but also restrain those directed toward pathogens and the commensal microbiota. Control of peripheral immune homeostasis by Tregs relies on their capacity to accumulate at inflamed sites and appropriately adapt to their local environment. To date, the factors involved in the control of these aspects of Treg physiology remain poorly understood. Here, we show that the canonical Th2 transcription factor GATA3 is selectively expressed in Tregs residing in barrier sites including the gastrointestinal tract and the skin. GATA3 expression in both murine and human Tregs was induced upon TCR and IL-2 stimulation. Although GATA3 was not required to sustain Treg homeostasis and function at steady state, GATA3 played a cardinal role in Treg physiology during inflammation. Indeed, the intrinsic expression of GATA3 by Tregs was required for their ability to accumulate at inflamed sites and to maintain high levels of Foxp3 expression in various polarized or inflammatory settings. Furthermore, our data indicate that GATA3 limits Treg polarization toward an effector T cell phenotype and acquisition of effector cytokines in inflamed tissues. Overall, our work reveals what we believe to be a new facet in the complex role of GATA3 in T cells and highlights what may be a fundamental role in controlling Treg physiology during inflammation., info:eu-repo/semantics/published

Published
2011

50. Microbe-dendritic cell dialog controls regulatory T-cell fate.

Author

Grainger, John R, Hall, Jason A., Bouladoux, Nicolas, Oldenhove, Guillaume, Belkaid, Yasmine, Grainger, John R, Hall, Jason A., Bouladoux, Nicolas, Oldenhove, Guillaume, and Belkaid, Yasmine

Abstract

Each microenvironment is controlled by a specific set of regulatory elements that have to be finely and constantly tuned to maintain local homeostasis. These environments could be site specific, such as the gut environment, or induced by chronic exposure to microbes. Various populations of dendritic cells are central to the orchestration of this control. In this review, we discuss some new findings associating dendritic cells from defined compartments with the induction and control of regulatory T cells in the context of exposure to both commensal and pathogenic microbes., FLWIN, info:eu-repo/semantics/published

Published
2010

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