Academic literature on the topic 'Type 1 regulatory T (Tr1) cells'
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Journal articles on the topic "Type 1 regulatory T (Tr1) cells"
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Yu, Hua, Nicola Gagliani, Harumichi Ishigame, Samuel Huber, Shu Zhu, Enric Esplugues, Kevan C. Herold, Li Wen, and Richard A. Flavell. "Intestinal type 1 regulatory T cells migrate to periphery to suppress diabetogenic T cells and prevent diabetes development." Proceedings of the National Academy of Sciences 114, no. 39 (September 11, 2017): 10443–48. http://dx.doi.org/10.1073/pnas.1705599114.
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Growing insight into the pathogenesis of autoimmune diseases and numerous studies in preclinical models highlights the potential of regulatory T cells to restore tolerance. By using non-obese diabetic (NOD) BDC2.5 TCR-transgenic (Tg), and IL-10 and Foxp3 double-reporter mice, we demonstrate that alteration of gut microbiota during cohousing experiments or treatment with anti-CD3 mAb significantly increase intestinal IL-10–producing type 1 regulatory T (Tr1) cells and decrease diabetes incidence. These intestinal antigen-specific Tr1 cells have the ability to migrate to the periphery via a variety of chemokine receptors such as CCR4, CCR5, and CCR7 and to suppress proliferation of Th1 cells in the pancreas. The ability of Tr1 cells to cure diabetes in NOD mice required IL-10 signaling, as Tr1 cells could not suppress CD4+ T cells with a dominant-negative IL-10R. Taken together, our data show a key role of intestinal Tr1 cells in the control of effector T cells and development of diabetes. Therefore, modulating gut-associated lymphoid tissue to boost Tr1 cells may be important in type 1 diabetes management.
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Almanan, Maha A., Jana Raynor, Claire Chougnet, Nathan Salamonis, Surya Amarachintha, Kris Steinbrecher, and David A. Hildeman. "Type 1 regulatory T cells (Tr1) homeostasis and function in aging." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 154.10. http://dx.doi.org/10.4049/jimmunol.198.supp.154.10.
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Abstract Type 1 regulatory T cells (Tr1) are a unique population of CD4+ Foxp3− cells that express high levels of IL-10, and have been defined based on their expression of CD49b and LAG-3. Despite the critical roles played by Tr1 cells in controlling T cell responses in autoimmunity and infection, the mechanisms underlying the homeostasis of Tr1 cells remain unclear. Here, we investigated the homeostasis, phenotype and function of Tr1 cells with age. We found that Tr1 cells accumulated dramatically with age. Further, Tr1 cells produced more IL-10 per cell compared to Foxp3+ Treg. While aged Tr1 cells expressed significant levels of c-Maf and Egr-2, two of the Tr1 defining transcription factors, they largely lacked expression of CD49b and were heterogeneous in LAG-3 and ICOS expression. Despite this heterogeneity, LAG-3 identified a population of aged Tr1 cells that potently inhibited T-cell proliferation in a partially IL-10-dependent manner in vitro and controlled colitis severity in vivo. Additional flow cytometric analysis revealed that roughly half of the IL-10 producing cells co-produced IFN-γ. Further, single cell mRNA-seq analysis revealed that IL-10+IFN-γ− cells had a TGF-beta signature, while IL-10+IFN-γ+ cells had a STAT4 signature. Strikingly, IL-6 was critical for overall Tr1 cell accumulation, as aged IL-6 KO mice showed a profound reduction in Tr1 cells and their expression of c-Maf. Combined, these data show that IL-6 promotes Tr1 accumulation with age and provide a new insight into a novel feedback loop whereby an inflammatory cytokine drives accrual of an anti-inflammatory cell population.
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Pot, Caroline, Lionel Apetoh, and Vijay K. Kuchroo. "Type 1 regulatory T cells (Tr1) in autoimmunity." Seminars in Immunology 23, no. 3 (June 2011): 202–8. http://dx.doi.org/10.1016/j.smim.2011.07.005.
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Huang, Weishan, Nicholas Koylass, and Avery August. "The non-receptor tyrosine kinase ITK is required for type 1 regulatory T cell development." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 133.36. http://dx.doi.org/10.4049/jimmunol.196.supp.133.36.
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Abstract Type 1 regulatory T (Tr1)cells lack the expression of Foxp3 but are potent producers of the immunosuppressive cytokine IL-10, with profound regulatory function in suppressing inflammation and promoting tolerance. Tr1 cells differentiate in response to signals engaging T cell receptor (TCR) and/or regulatory cytokine milieu. The non-receptor tyrosine kinase ITK is a key modulator downstream of TCR, playing critical role in T cell development and function. Using mouse models carrying Foxp3-RFP and IL-10-GFP dual reporters, we found that, in the absence of ITK, Foxp3− IL-10+ Tr1 cell development driven by TCR activation is severely impaired in various tissues (spleen, lymph nodes, lung, gut, and fat). Under Tr1 polarizing condition, naïve Foxp3− CD4+T cells isolated from WT mouse thymus and spleen can both give rise to Tr1cells, however, Itk−/− thymic and splenic naïve Foxp3− CD4+ T cells are deficient in Tr1 differentiation. Although Itk−/−CD4+ T cells proliferated under Tr1 differentiating conditions, they failed to up-regulate LAG3, CD49b, ICOS, PD-1, c-Maf, AHR, and IRF4 to levels observed in WT cells, suggesting that ITK is critical for Tr1 cell fate programming. Utilizing transgenic mouse model carrying an allele sensitive mutant of ITK that allows ITK kinase specific blockade by a small molecule 3MB-PP1, we also determined that the expression of the aforementioned markers is dependent on ITK kinas activity. Inhibiting ITK kinase activity also diminished Tr1 differentiation inhuman CD4+ T cells. We conclude that ITK is required for Tr1 cell development and targeting ITK signaling may be a strategy to modulate regulatory immunity for clinical benefit.
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McGuirk, Peter, Chantelle McCann, and Kingston H. G. Mills. "Pathogen-specific T Regulatory 1 Cells Induced in the Respiratory Tract by a Bacterial Molecule that Stimulates Interleukin 10 Production by Dendritic Cells." Journal of Experimental Medicine 195, no. 2 (January 21, 2002): 221–31. http://dx.doi.org/10.1084/jem.20011288.
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Antigen-specific T helper type 1 (Th1) cells mediate protective immunity against a range of infectious diseases, including that caused by Bordetella pertussis. Distinct T cell subtypes that secrete interleukin (IL)-10 or tumor growth factor (TGF)-β are considered to play a role in the maintenance of self-tolerance. However, the antigens recognized by these regulatory T cells in vivo have not been defined. Here we provide the first demonstration of pathogen-specific T regulatory type 1 (Tr1) cells at the clonal level and demonstrate that these cells are induced at a mucosal surface during an infection where local Th1 responses are suppressed. Tr1 clones specific for filamentous hemagglutinin (FHA) and pertactin were generated from the lungs of mice during acute infection with B. pertussis. The Tr1 clones expressed T1/ST2 and CC chemokine receptor 5, secreted high levels of IL-10, but not IL-4 or interferon (IFN)-γ, and suppressed Th1 responses against B. pertussis or an unrelated pathogen. Furthermore, FHA inhibited IL-12 and stimulated IL-10 production by dendritic cells (DCs), and these DCs directed naive T cells into the regulatory subtype. The induction of Tr1 cells after interaction of a pathogen-derived molecule with cells of the innate immune system represents a novel strategy exploited by an infectious pathogen to subvert protective immune responses in vivo.
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Dieckmann, Detlef, Cord Henrik Bruett, Heidi Ploettner, Manfred Bernhard Lutz, and Gerold Schuler. "Human CD4+CD25+ Regulatory, Contact-dependent T Cells Induce Interleukin 10–producing, Contact-independent Type 1-like Regulatory T Cells." Journal of Experimental Medicine 196, no. 2 (July 15, 2002): 247–53. http://dx.doi.org/10.1084/jem.20020642.
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It has been recently demonstrated that regulatory CD4+CD25+ CD45RO+ T cells are present in the peripheral blood of healthy adults and exert regulatory function similar to their rodent counterparts. It remains difficult to understand how the small fraction of these T cells that regulate via direct cell-to-cell contact and not via secretion of immunosuppressive cytokines could mediate strong immune suppression. Here we show that human CD4+CD25+ T cells induce long-lasting anergy and production of interleukin (IL)-10 in CD4+CD25− T cells. These anergized CD4+CD25− T cells then suppress proliferation of syngenic CD4+ T cells via IL-10 but independent of direct cell contact, similar to the so-called type 1 regulatory T (Tr1) cells. This ‘catalytic’ function of CD4+CD25+ T cells to induce Tr1-like cells helps to explain their central role for the maintenance of immune homeostasis.
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Garcia, Carlos Armando, Kunal Rehani, and Michael Martin. "Inhibition of glycogen synthase kinase-3 promotes human CD4+ T regulatory type 1 activity (88.48)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S148. http://dx.doi.org/10.4049/jimmunol.178.supp.88.48.
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Abstract T regulatory type 1 cells (Tr1) are a distinct subset of a heterogeneous population of regulatory CD4+ T cells present in humans whose main function is to prevent chronic immune activation and maintain normal immune homeostasis via the production of interleukin-10 (IL-10). Although several studies have identified particular in vitro conditions that promote Tr1 differentiation, none to date have identified a putative molecule when pharmacologically targeted promotes Tr1 differentiation. Identifying such a target has proven difficult due to the inherent complexity and lack of information regarding IL-10 gene regulation in T cells. In the present study, we examined the influence of the serine/threonine kinase, glycogen synthase kinase-3 (GSK3) to regulate IL-10 production by CD4+ T cells. CD3 stimulated peripheral blood mononuclear cells (PBMCs) or CD4+ T cells treated with GSK3 inhibitors promotes IL-2 and IL-10 production while suppressing interferon-gamma (IFN-?) levels as compared to cells treated with anti-CD3 alone. The ability of GSK3 inhibition to promote IL-10 and suppress IFN-? production in CD4+ T cells was restricted to the memory (CD45RA− CD45RO+) population of CD4+ T cells, whereas naïve (CD45RA+ CD45RO-) CD4+ T cells solely increased IL-2 production. Memory CD4+ T cells activated in the presence of GSK3 inhibition acquired the capacity to suppress the bystander activation of CD4+ T cells; an effect dependent on the presence of IL-10. Our findings illustrate a dichotomy present in the role of GSK3 in naïve and memory CD4+ T cells and identify GSK3 as a key kinase in Tr1 differentiation.
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Roessner, Philipp M., Laura Llaó Cid, Ekaterina Lupar, Tobias Roider, Marie Bordas, Christoph Schifflers, Lavinia Arseni, et al. "EOMES and IL-10 regulate antitumor activity of T regulatory type 1 CD4+ T cells in chronic lymphocytic leukemia." Leukemia 35, no. 8 (February 1, 2021): 2311–24. http://dx.doi.org/10.1038/s41375-021-01136-1.
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AbstractThe transcription factor eomesodermin (EOMES) promotes interleukin (IL)-10 expression in CD4+ T cells, which has been linked to immunosuppressive and cytotoxic activities. We detected cytotoxic, programmed cell death protein-1 (PD-1) and EOMES co-expressing CD4+ T cells in lymph nodes (LNs) of patients with chronic lymphocytic leukemia (CLL) or diffuse large B-cell lymphoma. Transcriptome and flow cytometry analyses revealed that EOMES does not only drive IL-10 expression, but rather controls a unique transcriptional signature in CD4+ T cells, that is enriched in genes typical for T regulatory type 1 (TR1) cells. The TR1 cell identity of these CD4+ T cells was supported by their expression of interferon gamma and IL-10, as well as inhibitory receptors including PD-1. TR1 cells with cytotoxic capacity accumulate also in Eµ-TCL1 mice that develop CLL-like disease. Whereas wild-type CD4+ T cells control TCL1 leukemia development after adoptive transfer in leukopenic Rag2−/− mice, EOMES-deficient CD4+ T cells failed to do so. We further show that TR1 cell-mediated control of TCL1 leukemia requires IL-10 receptor (IL-10R) signaling, as Il10rb-deficient CD4+ T cells showed impaired antileukemia activity. Altogether, our data demonstrate that EOMES is indispensable for the development of IL-10-expressing, cytotoxic TR1 cells, which accumulate in LNs of CLL patients and control TCL1 leukemia in mice in an IL-10R-dependent manner.
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Zhang, Ping, Jason S. Lee, Kate H. Gartlan, Iona S. Schuster, Iain Comerford, Antiopi Varelias, Md Ashik Ullah, et al. "Eomesodermin promotes the development of type 1 regulatory T (TR1) cells." Science Immunology 2, no. 10 (April 7, 2017): eaah7152. http://dx.doi.org/10.1126/sciimmunol.aah7152.
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Anannya, Orchi, and Avery August. "Interleukin-2 inducible T cell kinase functions as a molecular switch to fine tune differentiation of naive T helper cells in pro/anti-inflammatory effector T cell lineages." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 98.04. http://dx.doi.org/10.4049/jimmunol.206.supp.98.04.
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Abstract Naïve CD4+ T helper cells differentiate into effector CD4+ T cells with pro/anti-inflammatory functions upon receipt of signals from the T cell receptor (TCR) in presence of cytokines in the environment. Interleukin-2 inducible T cell kinase (ITK) has been shown to control the strength of signals downstream of the TCR. Here we have investigated the potential of ITK to act as a molecular switch in controlling T cell differentiation fate. Our results demonstrate in the absence of ITK expression/activity, naïve CD4+ T cells activated under conditions that promote differentiation into pro-inflammatory T helper type-17 (Th17) cells fail to differentiate into Th17 cells and instead switch into T cells expressing the T regulatory (Treg) lineage specific transcription factor Forkhead Box P3 (FoxP3). Similarly, we found that naïve CD4+ T cells activated to differentiate into anti-inflammatory Type 1 regulatory (Tr1) cells in the absence of ITK expression/activity fail to differentiate into Tr1 cells and instead switch into expressing the T helper type-1 (Th1) lineage specific T-box transcription factor (T-Bet). The switched FoxP3 expressing T cells resemble Tregs by their expression of Treg specific markers and have anti-inflammatory properties in suppressing effector T cell proliferation. In addition the switched T-Bet expressing T cells resemble Th1 cells by their expression of Th1 specific markers and the Th1 effector cytokine Interferon γ (IFNγ). This work suggest that signals regulated by ITK may function as a molecular switch to control Th17/Treg and Tr1/Th1 axes, highlighting the potential of manipulating ITK to control the balance of pro/anti-inflammatory T cells in immune disorders.
Dissertations / Theses on the topic "Type 1 regulatory T (Tr1) cells"
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PULVIRENTI, NADIA. "ROLE OF EOMES+ TYPE 1 REGULATORY T-CELLS IN MULTIPLE SCLEROSIS." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2022. http://hdl.handle.net/10281/393993.
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La sclerosi multipla (SM) è una malattia degenerativa autoimmune del Sistema Nervoso Centrale (SNC), in cui cellule T CD4 autoreattive attaccano la mielina dei neuroni causando danni al SNC. La SM è anche associata all’infezione del virus Epstein-Barr (EBV), ma il ruolo dei virus nella progressione della SM è dibattuto. Le risposte di cellule T autoreattive e anti-virali sono controllate da popolazioni diverse di cellule T regolatorie, quali le Treg FOXP3+ e le cellule T regolatorie di tipo 1 (Tr1). Entrambe le polazioni sono coinvolte nella SM, ma il ruolo delle cellule Tr1 nella SM in vivo è poco chiaro. L'eomesodermina (Eomes), un fattore di trascrizione che definisce il lineage delle cellule Tr1 e controlla l'espressione del granzima (Gzm)K, ci permette la loro identificazione ex vivo. La soppressione delle risposte immunitarie è mediata da queste cellule dopo attivazione antigenica tantochè la loro specificità antigenica ne è un fattore chiave. Terapie cellulari con cellule regolatorie sono attualmente già in uso clinico per altre malattie immunomediate ma per la SM è ancora necessario determinare quale subset cellulare sia in grado di sopprimere la risposta immunitaria.
Lo scopo di questa tesi è capire il ruolo delle cellule Tr1 nella SM, in particolare, analizzare le loro capacità migratorie verso SNC e la loro specificità per antigeni autologhi o virali, al fine di identificare una popolazione adatta per una eventuale terapia cellulare. Pertanto, in questo progetto ho monitorato una coorte di pazienti MS recidivanti-remittenti trattati o meno con Natalizumab ‒ anticorpo che blocca l’ingresso dei linfoci T nel SNC ‒ mediante tecniche di citofluorimetrica multidimensionale.
Ho mostrato che nel liquor di pazienti MS attivi le cellule Tr1 GzmK+ Eomes+ sono fortemente e selettivamente arricchite suggerendo un loro ruolo nelle ricadute. Inoltre, le Tr1 risultano ridotte nel sangue dei pazienti MS e con un’alta proliferanzione in vivo, suggerendo che le Tr1 siano reclutate e attivate nel SNC di questi pazienti. Coerentemente, nei pazienti SM trattati con Natalizumab, le Tr1 hanno frequenze e tassi di proliferazione normali. Al contrario, i pazienti SM hanno un numero maggiore di Treg che però sono meno proliferanti in vivo, mentre le CTL restano inalterate. Nei pazienti MS le cellule Tr1 rispondono fortemente e selettivamente all'antigene EBNA-1 associato alla latenza di EBV mentre la risposta è debole negli individui sani. Non si rileva invece alcuna risposta agli antigeni della mielina o del John Cunningham Virus. Inoltre i pazienti trattati con Natalizumab hanno livelli significativamente più elevati di Tr1 specifiche per EBV/EBNA1, suggerendo che le Tr1 EBV-specifiche siano reclutate e/o generate da precursori nel SNC. Le Tr1 mostrano maggiori proprietà antinfiammatorie nei pazienti SM secernendo livelli più alti di IL-10 in risposta a stimolazione policlonale. Infine abbiamo rilevato che nel liquor le Tr1 producono notevoli quantità di IL-10, come avviene anche nel sangue periferico di pazienti SM in risposta a EBV/ EBNA1 .
Nel complesso, i risultati supportano l'ipotesi di una risposta immunitaria anti-EBV alterata nel SNC dei pazienti SM, e suggeriscono un doppio ruolo per le cellule Tr1 Eomes: esse possono avere un ruolo benefico nelle ricadute in quanto sono presenti nel SNC e producono la citochina anti-infiammatoria IL-10 ma allo stesso tempo, la specificità per EBV nella fase latente potrebbe essere alla base di una risposta inefficiente al virus e quindi della progressione della MS. Ulteriori indagini sulle cellule Tr1 sono necessarie per comprendere le loro capacità soppressive, i geni coinvolti e il loro ruolo nella SM progressiva.Multiple sclerosis (MS) is a degenerative autoimmune disease of the Central Nervous System (CNS), where autoreactive CD4+T-cells are believed to attack the myelin sheath of neurons causing CNS damage. MS is also associated with viral infections, in particular with Epstein–Barr Virus (EBV), but the role of viruses in MS progression is debated. Auto-reactive and overshooting anti-viral T-cell responses are controlled by regulatory T-cell subsets, namely FOXP3+Treg and IL-10-producing type 1 regulatory cells (Tr1) cells. Both subsets were proposed to be involved in MS, but the role of Tr1 cells in vivo in MS remains unclear. Eomesodermin (Eomes), a putative lineage-defining transcription factor of Tr1 cells that controls directly the expression of Granzyme (Gzm)K, allows their analysis ex vivo. Notably, in order to suppress immune responses efficiently, regulatory T-cells have to be activated by antigens, and their antigen specificity is a key feature. Cell-therapy with regulatory T-cells was established in other immune-mediated diseases, but the subset that efficiently suppresses pathogenic T-cells in MS needs first to be identified. The aim of this thesis is to understand the role of Tr1-cells in MS, in particular, to analyze their CNS-homing capacities and their specificity for self- or viral-antigens, in order to identify subsets that are suited for MS cell-therapy. Therefore, in this project I monitored a cohort of relapsing-remitting MS patient that were either untreated or treated with Natalizumab ‒ the anti-α4 integrin antibody that block the CNS-homing of lymphocytes ‒ by multidimensional cytometric analysis. I found that GzmK+Tr1 cells ‒ and not FOXP3+Treg or GzmB+CTL (cytotoxic lymphocytes) ‒ are strongly and selectively enriched in the cerebrospinal fluid (CSF) of active MS patients, suggesting a role in relapses. Moreover, Tr1 cells were reduced in the blood of MS patients and were highly proliferating in vivo, suggesting that Tr1 cells are recruited and activated in the CNS of MS patients. Consistently, Natalizumab-treated MS patients showed normal Tr1 frequencies and proliferation rates. Conversely, MS patients had strikingly higher frequencies of Tregs and a reduced in vivo turnover, while CTL were unaltered. To assess ex vivo the antigen specificity, a new assay was successfully established. Tr1 and their putative precursors cells responded strongly and selectively to the EBV latency-associated antigen EBNA1 in MS patients, and not with lytic ones, but responded only weakly in healthy individuals. They also failed to respond to myelin antigens or to the John Cunningham Virus. Interestingly, Natalizumab-treated patients had significantly higher levels of EBV-specific Tr1 cells, suggesting that these cells are recruited to and/or generated from precursors in the CNS. Tr1 cells have enhanced anti-inflammatory properties in MS patients, secreting higher levels of IL-10 in response to polyclonal stimulation. Moreover, we have preliminary evidences that Tr1 cells produce also considerable amounts of IL-10 in the CSF and even in response to EBV/EBNA1 in the blood of MS patients. Overall, our results are consistent with the notion that there is a dysregulated immune response against EBV in the CNS of MS patients, and suggest a dual role for Eomes+Tr1 cells regulating EBV-specific and not myelin-reactive T-cells. A key finding for this project is that Tr1 cells may have a beneficial role in relapses since they are present in the CNS and produce the anti-inflammatory cytokine IL-10. But at the same time, the specificity for EBV in the latent phase could be at the basis of the inefficient response to the virus and therefore of MS progression. In the future a better understanding of Tr1 cell role in MS could lead to novel therapeutic approaches, although further investigations on Tr1 cells are needed to understand their suppressive abilities, the genes involved and their role in progressive MS.
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Sutavani, Ruhcha V. "CD55 costimulation induces differentiation of human T regulatory type - 1 (Tr1) cells." Thesis, University of Nottingham, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.727951.
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Unlike other helper T cells, the co-stimulatory ligands responsible for T regulatory type-1 (Trl) cells differentiation remain undefined. Understanding the molecular interactions driving peripheral Trl differentiation is important because Trls potently regulate immune responses, by IL-10 production. In this study we show that co-stimulation of human naïve CD4+ cells through the CD97-CD55 interaction drives Trl activation, expansion and function. T cell activation and expansion was equipotent with CD55 or CD28 co-stimulation, however CD55 co-stimulation resulted in two IL-10 secreting populations. The majority of the IL-10 was secreted by the minor, Trl population (IL-10high IFN-y- IL-4-, <5% cells) that express Trl markers CD49b, LAG-3 and CD226. This Tr 1 phenotype was not re-stimulated by CD28. But on CD55 re-stimulation, Trls proliferated and maintained their differentiated IL-10 high phenotype. The Trls significantly suppressed effector T cell function in an IL-10 dependent manner. The remaining (>95%) cells adopted a Thl- like IFN-y + phenotype. However, in contrast to CD28 derived This, CD55 derived This demonstrated increased plasticity with the ability to co-express IL-10 when re-stimulated through CD55 or CD28. These data identify CD55 as a novel co-stimulator of human Trls and support a role for alternative co-stimulatory pathways in determining the fate of the growing number of T helper populations. In this study we also show a defect in Trls in the autoimmune disease Multiple Sclerosis (MS). In response to CD55 costimulation, naïve CD4+ cells from a cohort of MS patients did not differentiate into Trl cells as normal, however the CD55 induced Thl response was unaffected. These patients showed persistent lack of an IL-10h1gh Trl population on primary and secondary CD55 costimulation. Also, MS patients mounted stronger IFN-y responses compared to healthy controls. These data demonstrate an altered immune balance in MS and highlight a defect in the Trl response as a contributing factor of this change. Overall, this study demonstrates that CD55 acts as a potent co-stimulator and activator of human naive CD4+ cells resulting in the differentiation of a discrete Trl population that inhibits T cell function in an IL-10 dependent manner and maintains the Trl phenotype upon re-stimulation, in healthy individuals. However, there is a defect in this normal Tr 1 response in the autoimmune condition Multiple Sclerosis.
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MAGNANI, CHIARA FRANCESCA. "Type 1 regulatory T cells: cytotoxic activity and molecular signature." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2010. http://hdl.handle.net/10281/20197.
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IL-10-producing CD4+ type 1 regulatory T (Tr1) cells, defined based on their ability to produce high levels of IL-10 in the absence of IL-4, are major players in the induction and maintenance of peripheral tolerance. Tr1 cells inhibit T cell responses mainly via cytokine dependent mechanisms. The cellular and molecular mechanisms underlying the suppression of APC by Tr1 cells are still not completely elucidated. Here, we defined that Tr1 cells specifically lyse myeloid APC through a granzyme B (GZB)- and perforin (PRF)- dependent mechanism that requires HLA class I recognition, CD54/Lymphocyte Function-associated Antigen (LFA)-1 adhesion, and activation via CD2. Notably, interaction between CD226 on Tr1 cells and their ligands on myeloid cells, leading to Tr1 cell activation, is necessary for defining Tr1 cell target specificity. We also showed that high frequency of GZB expressing CD4+ T cells is detected in tolerant patients and correlates with elevated occurrence of IL-10- producing CD4+ T cells. In conclusion, the modulatory activities of Tr1 cells are not only due to suppressive cytokines but also to specific cell-to-cell interactions which lead to selective killing of target cells and possibly bystander suppression. Adaptive type 1 regulatory T (Tr1) cells are suppressor cells characterized by the production of IL-10 in the absence of IL-4 and by the ability to suppress immune responses mainly by the release of IL- 10 and TGF-β. Despite several efforts for the detection of molecular markers of Tr1 cells have been made, so far Tr1 cell identification relies on cytokine production profile. Moreover, to date no master regulator gene for Tr1 cells have been defined. To identify Tr1 cell specific surface biomarkers, master regulator genes, and molecules involved in their suppressive functions, we performed a gene expression profiling to compare the gene expression of ex vivo isolated Tr1 cell clones compare to Th0 cell clones, in resting state and upon TCR activation. Results demonstrated that Tr1 cells signature is of anti-inflammation, anti-proliferation, and immuno-modulation. In addition, we identified surface molecules that could be useful to identify Tr1 cell population. Interestingly, several transcription factors resulted differentially expressed in Tr1 cells compared to Th0 cells, which may represent master regulators of Tr1 cells.
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Martire, Delphine. "Potentiel thérapeutique des lymphocytes régulateurs de type 1 (Tr1) dans l'arthrite expérimentale." Thesis, Montpellier 1, 2013. http://www.theses.fr/2013MON1T025.
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Objectifs : Les lymphocytes T régulateurs de par leur rôle primordial dans l'homéostasie de la réponse immune sont des cellules idéales pour une immunothérapie antigène-spécifique dans les maladies auto-immunes. Les lymphocytes T régulateurs de type 1 ou Tr1 sont caractérisées par une forte sécrétion d'IL-10, cytokine qui joue un rôle déterminant dans leur capacité à supprimer des réponses immunes pathologiques dans différents contextes. L'objectif de ma thèse est d'évaluer le potentiel thérapeutique de cellules Tr1 spécifiques du collagène de type II (col-Treg) dans deux modèles de polyarthrite rhumatoïde (PR) chez la souris. Méthode : Les clones Col-Treg ne possèdent pas de marqueurs membranaires spécifiques mais sont caractérisés par un profil cytokinique particulier (IL10highIL4negIFN-γint) et par leur capacité de suppression in vitro. Tout comme les Tregs naturels, ils expriment une quantité importante de GITR, de CD39 et de Granzyme B. Une simple injection de cellules Col-Treg réduit l'incidence et les symptômes cliniques de l'arthrite à la fois de manière préventive et curative, avec un impact significatif sur les anticorps anti-collagène de type II. En outre, l'injection de Tr1 antigène spécifique in vivo diminue de manière significative la prolifération des cellules T antigène spécifique. Conclusion : Nos résultats démontrent le potentiel thérapeutique des cellules Col-Treg dans deux modèles d'arthrite expérimentale prouvant que les cellules Col-Treg représente une nouvelle approche thérapeutique de choix pour le traitement des patients atteint de polyarthrite et réfractaires aux traitements actuelsObjectives : Regulatory T (Treg) cells play a crucial role in preventing autoimmune diseases and are an ideal target for therapies to suppress inflammation in an antigen-specific manner. Type 1 Treg cells (Tr1) are defined by their capacity to produce high levels of IL10, which contributes to their ability to suppress pathological immune responses in several settings. The aim of my PhD was to evaluate the therapeutic potential of collagen type II-specific Tr1 (Col-Treg) cells in two models of rheumatoid arthritis (RA) in mice. Methods : Col-Treg clones were isolated and expanded from Collagen-specific TCR transgenic mice. Their cytokine secretion profile and phenotype characterization were studied. The therapeutic potential of Col-Treg cells was evaluated after adoptive transfer in collagen-antibodies- and collagen-induced arthritis models. The in vivo suppressive mechanism on effector T cell proliferation was also investigated. Results : Col-Treg clones are characterized by a cytokine profile (IL10highIL4negIFN-γint) and mediate contact-independent immune suppression. They also share with natural Tregs high expression of GITR, CD39 and Granzyme B. Single infusion of Col-Treg cells reduced incidence and clinical symptoms of arthritis both in preventive and curative settings, with a significant impact on collagen type II antibodies. Importantly, injection of antigen-specific type 1 Treg cells decreases significantly the proliferation of antigen-specific effector T cells in vivo. Conclusion : Our results demonstrate the therapeutic potential of Col-Treg cells in two models of RA, providing evidence that Col-Treg could be an efficient cell-based therapy for RA patients refractory to current treatments
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Lindley, Shelley Maria. "Regulatory and effector T cells in type 1 diabetes." Thesis, King's College London (University of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.430014.
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Goudy, Kevin Scott Tisch Roland M. "Characterization and immunomodulation of regulatory T cells in Type 1 diabetes." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2008. http://dc.lib.unc.edu/u?/etd,2058.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2008.Title from electronic title page (viewed Feb. 17, 2009). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Microbiology and Immunology." Discipline: Microbiology and Immunology; Department/School: Medicine.
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Hooper, Kirsten Mary. "PGE2 AND IL-27: NOVEL PROINFLAMMATORY MECHANISMS INVOLVING DENDRITIC CELLS AND TYPE 1 REGULATORY T CELLS." Diss., Temple University Libraries, 2017. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/432693.
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Microbiology and ImmunologyPh.D.
Interleukin-27 (p28/EBI3) is an immunomodulatory cytokine expressed by activated antigen presenting cells. Although first discovered to be involved in Th1 cell differentiation, further studies demonstrated the immunosuppressive functions of IL-27 including inhibition of Th2 and Th17 differentiation, development of a tolerogenic phenotype in dendritic cells (DC), and promoting type 1 regulatory T cells (Tr1). The anti-inflammatory effects of IL-27 have been demonstrated in vivo in murine models of parasitic infections and autoimmune diseases. Despite the prevalence of studies detailing the induction of IL-27 expression and the role of IL-27 in Tr1 differentiation, little is known about factors that negatively regulate IL-27 expression and Tr1 differentiation. Prostaglandin E2 (PGE2), a lipid mediator abundant at inflammatory sites, was shown to act as a proinflammatory agent in models of inflammatory/autoimmune diseases primarily by promoting CD4 Th1/Th17 differentiation. Here we describe a novel proinflammatory mechanism for PGE2 through the inhibition of IL-27 production in conventional dendritic cells (cDC) and the inhibition of Tr1 differentiation. PGE2 inhibits IL-27 production in bone marrow-derived DC and macrophages, as well as in splenic cDC, through EP2/EP4 receptors, induction of cAMP, and downregulation of IRF1 expression and binding to the p28 IL-27 ISRE site. The inhibitory effect of PGE2 on p28 and irf1 expression does not involve endogenous IFN-β, STAT1 or STAT2, and inhibition of IL-27 does not appear to be mediated through PKA, EPAC, PI3K, or MAPKs. We observed similar inhibition of p28 expression in vivo in splenic DC following administration of dimethyl PGE2 in conjunction with LPS. In addition to the inhibition of IL-27 production in APCs, PGE2 also directly affects Tr1 differentiation by reducing IL-27-induced CD4+CD49b+LAG-3+Foxp3- Tr1 cells and IL-10 production. The inhibitory effect is mediated by EP4 and induction of cAMP in differentiating CD4 T cells. IL-27-induced Tr1 differentiation and function depends primarily on the sustained expression of c-Maf in addition to AhR and Blimp-1. PGE2 significantly reduced expression of c-Maf without affecting AhR and only marginally reducing Egr-2/Blimp-1 expression. The effects of PGE2 on Tr1 cells are independent of STAT1/STAT3 signaling and of IL-21 signaling. In addition, the effect of PGE2 on CD4+CD49b+LAG-3+ Tr1 differentiation was not associated with either induction of Foxp3 or IL-17 production, suggesting a lack of transdifferentiation into Foxp3+ Treg or effector Th17 cells. The effects of PGE2 on both IL-27 production and IL-27-induced Tr1 differentiation represent novel proinflammatory mechanisms of PGE2.
Temple University--Theses
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Nikitin, Artemii. "Role of nuclear receptor RORα in regulatory T cells." Thesis, Université de Lille (2018-2021), 2019. http://www.theses.fr/2019LILUS073.
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Les facteurs de transcription de la superfamille des récepteurs nucléaires jouent de multiples rôles dans le développement et la fonction des lymphocytes T régulateurs (TREG). Les TREG sont des cellules régulatrices/suppressives qui contrôlent les réponses d’autres types cellulaires et l’homéostasie locale des tissus.Comme les TREG sont actives au sein de divers organes, tant à l’homéostasie qu’en conditions inflammatoires,ils doivent répondre à la fois aux contexte local au sein du tissus et à un environnement immunologiquement agressif tout en préservant leurs propriétés tolérogéniques au cours du temps. Ces caractéristiques apparemment antinomiques sont contrôlées par un réseau transcriptionnel complexe au sein duquel le facteur de transcription FOXP3 joue un rôle prédominant. Au cours des dernières années, de nombreuses études se sont intéressées aux TREG présent dans les tissus non lymphoïdes (NLT). Ces populations ont été étudiées aussi bien à l’homéostasie qu’en conditions inflammatoires dans diverses pathologies. Des facteurs de transcriptions spécifiques d’un tissus ou d’une fonction déterminées ont été mis en évidence et leur rôle régulateur dans le développement, l’activation, la migration et l’immunosuppression a été caractérisé. RORa est un récepteur nucléaire qui contrôle le développement cérebellaire et hépatique, le métabolisme systémique, la différenciation des lymphocytes auxiliaires TH17, des cellules lymphoïdes innées (ILC) de type 2 et 3. RORa est fortement exprimé dans les TREG des NLT, y compris dans le tissus adipeux viscéral (VAT), l’intestin et la peau. . . .Ces populations de TREG exprimant RORa ont été associées à diverses pathologies. Cependant seule une étude récente a été consacrée à leur rôle précis. L’implication de RORa dans de nombreuses fonction, sa forte expression au sein des TREG des NLT nous a poussé a étudier le rôle de ces TREG exprimant RORa dans diverses pathologies. Dans ce butit, nous avons généré des souris spécifiquement déficientes pour RORa au sein des TREG (RORaFoxp3/Foxp3 ). Nous avons émis l’hypothèse que RORa contrôle le développement ou la fonction des TREG en conditions homéostatiques et dans des pathologies inflammatoires des NLT. Aussi nous avons caractérisé le phénotype des animaux RORaFoxp3/Foxp3 et en particulier les TREG du VAT à l’homéostasie, où la réponse de type 2 est protectrice et dans un modèle d’obésité (et d’insulino-résistance) induit par l’obésité (DIO) dans laquelle nous avons mis en évidence un rôle protecteur important des TREG exprimant RORa dans ces deux conditions expérimentales. Nous également étudié la contribution de ces cellules dans un modèle d’inflammation allergique (AAI) induite par un acarien (HDM) caractérisé par une forte réponse de type 2 et montré une aggravation de la pathologie. Pour étudier le mécanisme moléculaire de l’action de RORa au sein des TREG, nous avons procédé à une analyse transcriptomique des cellules isolées dans diverses conditions expérimentales in vivo et in vitro et avons étudié le rôle de RORa dans les modifications épigénétiques au sein des TREG en caractérisation l’acétylation des histones dans le génome entier. Cette étude nous a permis de mieux appréhender comment les TREG étaient régulées par un facteur nucléaire à l’homéostasie et en conditions inflammatoires. Les récepteurs nucléaires représentent des cibles thérapeutiques intéressantes compte tenu de leur action pléiotropique et de leurs ligands de petite taille. Compte tenu de l’importance des TREG dans l’homéostasie tissulaire et dans de nombreuses pathologies, cibler de tels facteurs au sein d epopulations cellulaires spécifiques représente une stratégie prometteuse dans le case de RORa et des TREGTranscription factors of the nuclear receptor superfamily have a vast influence on development and function ofregulatory T cell (TREG) cells. TREG cells are suppressive immune cells of adaptive immune system. Their mainfunctions are control of inflammatory response mounted by other immune cells and maintenance of localtissue homeostasis. As TREG act at various sites of the body and both in homeostatic and inflammatory state,they need to adequately respond to local tissue-specific cues as well as adapt to aggressive immuneenvironments while preserving their long-lasting tolerogenic properties. This is achieved by weaving complextranscriptional networks, converging at transcription factors with various coordination functions, the mainbeing forkhead box P3 (FOXP3). During last few years, many studies focused on TREG cells found innon-lymphoid tissue (NLT). These populations of TREG are examined in the contexts of homeostasis and manyinflammatory diseases, and tissue- or function-specific transcription factor (TF) were assigned to some ofthem as regulators of development, activation, proliferation, stability, migration and suppressive functions.Retinoic acid receptor-related orphan receptor alpha (RORa) is a nuclear receptor, which controls cerebellumdevelopment, liver and whole-body metabolism and differentiation of T-helper (TH)17, type 2 innate lymphoidcells (ILC2) and type 3 innate lymphoid cells (ILC3). RORa is highly expressed in NLT TREG, includingpopulations in visceral adipose tissue (VAT), intestine and skin, and gets more and more mentions in thearticles dedicated to TREG in NLT. These RORa-expressing populations of TREG were all shown to be involvedin various pathologies. However, RORa role in TREG was directly addressed only once in a recent study. It’sactive involvement in various processes, high expression in NLT TREG and lack of knowledge make RORa anattractive target for investigation, to deepen current view of homeostasis control by TREG and thus betterunderstand mechanisms of development of associated diseases. To attain these objectives, a mouse strain withTREG-specific RORa deficiency was generated. Our central hypothesis is that RORa controls development orfunction of TREG cells in homeostasis of NLT and potentially in inflammatory diseases. For studying a role ofRORa in NLT TREG during control of tissue homeostasis, in particular, VAT TREG, we have charachterizedphenotype of untreated RORaFoxp3/Foxp3 mice and challenged mice with a model of diet-induced obesity(DIO). In both cases we have found an important role of TREG-expressed RORa. To further investigate a roleof RORa in TREG during pathologies and it’s contribution to various types of immune response we have testedan involvement of RORa in TREG in the model of allergic pathology, namely house dust mite (HDM)-inducedallergic airway inflammation (AAI) model.To elucidate molecular mechanisms of RORa action in TREG cells, we have performed gene expression profilingof TREG cells from examined tissues and conditions in vivo, as well as in vitro. We also have studied a role ofRORa in epigenetic landscape of TREG cells in vitro by probing histone acetylation marks genome wide. As aresult of this study, we have gained a broader understanding of TREG control by nuclear receptors and TF ingeneral in homeostatic conditions and during inflammation. Nuclear receptors proved to be useful targets fortherapeutic agents thanks to their versatile functions inside the cell and to ligand-dependency. Given thecrucial importance of TREG cells in organismal homeostasis and their involvement in numerous pathologies,targeting particular cues inside these cells may be a powerful tool in new treatment strategies. Results of ourstudy might serve as a basis for development of novel pharmaceutical agents targeting RORa
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Tonkin, Daniel R. "TGF-[beta]-induced regulatory T cells in type I diabetes : function and antigen dependence /." Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2007.
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Thesis (Ph.D. in Immunology) -- University of Colorado Denver, 2007.Typescript. Includes bibliographical references (leaves 182-202). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;
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Singh, Kailash. "Regulatory T cells in type 1 diabetes: the role of IL-35 in counteracting the disease." Doctoral thesis, Uppsala universitet, Institutionen för medicinsk cellbiologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-329524.
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Type 1 diabetes (T1D) is etiologically considered as an autoimmune disease, where insulin-producing β-cells are damaged by autoimmune attacks. Regulatory T (Treg) cells are immune homeostasis cells. In the present thesis I aimed to investigate the role of Treg cells and other immune cells in the early development of T1D. In order to do that, we first determined which immune cells that are altered at an early stage of the T1D development. We found that dendritic cells and plasmacytoid dendritic cells induce the initial immune response. Next, we investigated the role of Treg cells in multiple low dose streptozotocin (MLDSTZ) induced T1D and in NOD mice. We found that the numbers of Treg cells were increased in both MLDSTZ and NOD mice when the MLDSTZ mice were hyperglycemic. However, the increased Treg cells showed a decreased production of anti-inflammatory cytokines (IL-10, IL-35 and TGF-β) and an increased expression of pro-inflammatory cytokines (IFN-γ and IL-17a). These results revealed that Treg cells switch their phenotype under T1D conditions. IL-35 administration effectively prevented the development of, and reversed established MLDSTZ induced T1D. Treg cells from IL-35 treated mice showed an increased expression of the Eos transcription factor, accompanied by an increased expression of IL-35 and a decreased expression of IFN-γ and IL-17a. These data indicate that IL-35 administration counteracted the early development of T1D by maintaining the phenotype of the Treg cells. Furthermore, IL-35 administration reversed established T1D in the NOD mouse model by maintaining the phenotype of Treg cells, seemingly by inducing the expression of Eos. Moreover, the circulating level of IL-35 was significantly lowered in both new onset and long-standing T1D patients compared to healthy controls. In addition, patients with T1D with remaining C-peptide had significantly higher levels of IL-35 than patients lacking C-peptide, suggesting that IL-35 might prevent the loss of β-cell mass. In line with this hypothesis, we found that LADA patients had a higher proportion of IL-35+ tolerogenic antigen presenting cells than T1D patients. Subsequently, we determined the proportions of IL-35+ Treg cells and IL-17a+ Treg cells in T1D patients with diabetic nephropathy (DN), which were age, sex and BMI matched with healthy controls and T1D patients. The proportion of IL-35+ Treg cells was decreased in DN and T1D patients, but IL-17a+ Treg cells were more abundant than in healthy controls. Furthermore, we found that the number of Foxp3+ Treg cells was increased in the kidneys of MLDSTZ mice. However, infiltration of mononuclear cells was seen in kidneys of these mice. In addition, kidney tissues of IL-35 treated MLDSTZ mice did not show any mononuclear cell infiltration. These results demonstrate that IL-35 may be used to prevent mononuclear cell infiltration in kidney diseases. Our findings indicate that the numbers of Foxp3+ Treg cells are increased in T1D, but that these Treg cells fail to counteract the ongoing immune assault in islets and kidneys of hyperglycemic mice. This could be explained by a phenotypic shift of the Treg cells under hyperglycemic conditions. IL-35 administration reversed established T1D in two different animal models of T1D and prevented mononuclear cell infiltration in the kidneys by maintaining the phenotype of Treg cells.
Book chapters on the topic "Type 1 regulatory T (Tr1) cells"
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Battaglia, Manuela, Silvia Gregori, Rosa Bacchetta, and Maria Grazia Roncarolo. "Human Type 1 T Regulatory Cells." In Regulatory T Cells and Clinical Application, 455–71. New York, NY: Springer US, 2008. http://dx.doi.org/10.1007/978-0-387-77909-6_24.
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Roncarolo, Maria Grazia, Silvia Gregori, and Megan Levings. "Type 1 T Regulatory Cells and Their Relationship with CD4+ CD25+ T Regulatory Cells." In Novartis Foundation Symposia, 115–31. Chichester, UK: John Wiley & Sons, Ltd, 2008. http://dx.doi.org/10.1002/0470871628.ch9.
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McGee, Michael C., Avery August, and Weishan Huang. "TCR/ITK Signaling in Type 1 Regulatory T cells." In Advances in Experimental Medicine and Biology, 115–24. Singapore: Springer Singapore, 2021. http://dx.doi.org/10.1007/978-981-15-6407-9_7.
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Gregori, Silvia, Maria Grazia Roncarolo, and Rosa Bacchetta. "Methods for In Vitro Generation of Human Type 1 Regulatory T Cells." In Methods in Molecular Biology, 31–46. Totowa, NJ: Humana Press, 2010. http://dx.doi.org/10.1007/978-1-60761-869-0_3.
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Gregori, Silvia, Manuela Battaglia, and Maria-Grazia Roncarolo. "Re-Establishing Immune Tolerance in Type 1 Diabetes via Regulatory T Cells." In Novartis Foundation Symposia, 174–86. Chichester, UK: John Wiley & Sons, Ltd, 2008. http://dx.doi.org/10.1002/9780470697405.ch16.
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Piconese, Silvia, and Vincenzo Barnaba. "Stability of Regulatory T Cells Undermined or Endorsed by Different Type-1 Cytokines." In Advances in Experimental Medicine and Biology, 17–30. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-15774-0_2.
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Gu, Chao, and SangKon Oh. "Type 1 Regulatory T Cells and Their Application in Cell Therapy." In Regulatory T Cells [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.106852.
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Critical roles of regulatory T cells (Tregs) in the maintenance of immune homeostasis by controlling unwanted types of immune responses have been well documented. Therefore, Treg-based therapeutic strategies for inflammatory diseases have long been investigated. Type 1 regulatory T (Tr1) cells and Foxp3+ Tregs are two major subsets of regulatory CD4+ T cells. In contrast to Foxp3+ Tregs, the master transcription regulator for Tr1 cells still remains elusive. Nevertheless, Tr1 cells are generally defined as a specialized subset of CD4+ T cells, which are induced in the periphery during antigen exposure in tolerogenic condition. As one of their key features, Tr1 cells express immunosuppressive cytokine IL-10, which can repress the function of effector immune cells independently of Foxp3 expression. In this book chapter, we discuss the recent developments in the field of Tr1 cells, including major characteristics of Tr1 cells, methods for Tr1 induction as well as their therapeutic potentials in immune-mediated diseases.
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Brooks, Augustin. "Presentation and Natural History of Type 1 Diabetes." In Oxford Textbook of Endocrinology and Diabetes 3e, edited by John A. H. Wass, Wiebke Arlt, and Robert K. Semple, 1930–35. Oxford University Press, 2021. http://dx.doi.org/10.1093/med/9780198870197.003.0244.
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Type 1 diabetes results from loss of pancreatic β-cell function, producing a state of insulin insufficiency that results in spontaneous hyperglycaemia and ketone formation. Genetically susceptible individuals are believed to encounter an (as yet undefined) environmental trigger which initiates an autoimmune process, leading to autoantibody formation, activation of autoreactive T-lymphocytes and pancreatic β-cell destruction. Onset occurs at any age beyond 6 months, with two peak incidences at 5–7 years and during puberty. Incidence is increasing by 3–4% per year, implying a causative role for non-genetic factors. Symptomatic onset with polyuria, polydipsia, and weight loss later leads to presentation with diabetic ketoacidosis if untreated. The discovery of insulin transformed type 1 diabetes from a terminal disease to a manageable medical condition, although exogenous insulin replacement cannot fully mimic the natural regulatory ability of β-cells. Microvascular and macrovascular complications of chronically elevated glucose continue to cause premature morbidity and mortality, with mean reduction in life expectancy estimated at 11–13 years.
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Pearce, Simon H. S., and Catherine J. Owen. "Endocrine Autoimmunity." In Oxford Textbook of Endocrinology and Diabetes 3e, edited by John A. H. Wass, Wiebke Arlt, and Robert K. Semple, 50–58. Oxford University Press, 2021. http://dx.doi.org/10.1093/med/9780198870197.003.0007.
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The elucidation of the molecular basis for the rare monogenic polyendocrinopathy syndromes including autoimmune polyendocrinopathy type 1, has also allowed novel insights into key points of normal immune homeostasis such as thymic T-lymphocyte antigen receptor selection and the role of peripheral regulatory T cells. These fundamental advances have had far-reaching implications beyond those for endocrine patients. In contrast, the common, complex autoimmune endocrinopathies have been shown to be determined by numerous genetic variants within immune system receptors and signalling pathways along with a small number of variants in the target tissue antigens. A variety of environmental risk factors have been identified for several of these conditions, but it remains to be clarified how these impact pathogenesis at a molecular level. Moreover, the mainstay of therapies for these conditions is hormone replacement and there remains a ‘translational gap’ whereby information about disease pathogenesis has yet to be converted to useful patient advances.
Conference papers on the topic "Type 1 regulatory T (Tr1) cells"
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Zhang, Hongru, Jun Gui, Angelica Ortiz, and Serge Fuchs. "Abstract A100: Downregulation of type 1 interferon receptor (IFNAR1) regulates the balance of regulatory T cells (Tregs) and cytotoxic T lymphocytes (CTLs) in tumor microenvironment." In Abstracts: AACR Special Conference on Tumor Immunology and Immunotherapy; November 17-20, 2019; Boston, MA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/2326-6074.tumimm19-a100.
Full textReports on the topic "Type 1 regulatory T (Tr1) cells"
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Ficht, Thomas, Gary Splitter, Menachem Banai, and Menachem Davidson. Characterization of B. Melinensis REV 1 Attenuated Mutants. United States Department of Agriculture, December 2000. http://dx.doi.org/10.32747/2000.7580667.bard.
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Brucella Mutagenesis (TAMU) The working hypothesis for this study was that survival of Brucella vaccines was directly related to their persistence in the host. This premise is based on previously published work detailing the survival of the currently employed vaccine strains S19 and Rev 1. The approach employed signature-tagged mutagenesis to construct mutants interrupted in individual genes, and the mouse model to identify mutants with attenuated virulence/survival. Intracellular survival in macrophages is the key to both reproductive disease in ruminants and reticuloendothelial disease observed in most other species. Therefore, the mouse model permitted selection of mutants of reduced intracellular survival that would limit their ability to cause reproductive disease in ruminants. Several classes of mutants were expected. Colonization/invasion requires gene products that enhance host-agent interaction or increase resistance to antibacterial activity in macrophages. The establishment of chronic infection requires gene products necessary for intracellular bacterial growth. Maintenance of chronic infection requires gene products that sustain a low-level metabolism during periods characterized little or no growth (1, 2). Of these mutants, the latter group was of greatest interest with regard to our originally stated premise. However, the results obtained do not necessarily support a simplistic model of vaccine efficacy, i.e., long-survival of vaccine strains provides better immunity. Our conclusion can only be that optimal vaccines will only be developed with a thorough understanding of host agent interaction, and will be preferable to the use of fortuitous isolates of unknown genetic background. Each mutant could be distinguished from among a group of mutants by PCR amplification of the signature tag (5). This approach permitted infection of mice with pools of different mutants (including the parental wild-type as a control) and identified 40 mutants with apparently defective survival characteristics that were tentatively assigned to three distinct classes or groups. Group I (n=13) contained organisms that exhibited reduced survival at two weeks post-infection. Organisms in this group were recovered at normal levels by eight weeks and were not studied further, since they may persist in the host. Group II (n=11) contained organisms that were reduced by 2 weeks post infection and remained at reduced levels at eight weeks post-infection. Group III (n=16) contained mutants that were normal at two weeks, but recovered at reduced levels at eight weeks. A subset of these mutants (n= 15) was confirmed to be attenuated in mixed infections (1:1) with the parental wild-type. One of these mutants was eliminated from consideration due to a reduced growth rate in vitro that may account for its apparent growth defect in the mouse model. Although the original plan involved construction of the mutant bank in B. melitensis Rev 1 the low transformability of this strain, prevented accumulation of the necessary number of mutants. In addition, the probability that Rev 1 already carries one genetic defect increases the likelihood that a second defect will severely compromise the survival of this organism. Once key genes have been identified, it is relatively easy to prepare the appropriate genetic constructs (knockouts) lacking these genes in B. melitensis Rev 1 or any other genetic background. The construction of "designer" vaccines is expected to improve immune protection resulting from minor sequence variation corresponding to geographically distinct isolates or to design vaccines for use in specific hosts. A.2 Mouse Model of Brucella Infection (UWISC) Interferon regulatory factor-1-deficient (IRF-1-/- mice have diverse immunodeficient phenotypes that are necessary for conferring proper immune protection to intracellular bacterial infection, such as a 90% reduction of CD8+ T cells, functionally impaired NK cells, as well as a deficiency in iNOS and IL-12p40 induction. Interestingly, IRF-1-/- mice infected with diverse Brucella abortus strains reacted differently in a death and survival manner depending on the dose of injection and the level of virulence. Notably, 50% of IRF-1-/- mice intraperitoneally infected with a sublethal dose in C57BL/6 mice, i.e., 5 x 105 CFU of virulent S2308 or the attenuated vaccine S19, died at 10 and 20 days post-infection, respectively. Interestingly, the same dose of RB51, an attenuated new vaccine strain, did not induce the death of IRF-1-/- mice for the 4 weeks of infection. IRF-1-/- mice infected with four more other genetically manipulated S2308 mutants at 5 x 105 CFU also reacted in a death or survival manner depending on the level of virulence. Splenic CFU from C57BL/6 mice infected with 5 x 105 CFU of S2308, S19, or RB51, as well as four different S2308 mutants supports the finding that reduced virulence correlates with survival Of IRF-1-/- mice. Therefore, these results suggest that IRF-1 regulation of multi-gene transcription plays a crucial role in controlling B. abortus infection, and IRF-1 mice could be used as an animal model to determine the degree of B. abortus virulence by examining death or survival. A3 Diagnostic Tests for Detection of B. melitensis Rev 1 (Kimron) In this project we developed an effective PCR tool that can distinguish between Rev1 field isolates and B. melitensis virulent field strains. This has allowed, for the first time, to monitor epidemiological outbreaks of Rev1 infection in vaccinated flocks and to clearly demonstrate horizontal transfer of the strain from vaccinated ewes to unvaccinated ones. Moreover, two human isolates were characterized as Rev1 isolates implying the risk of use of improperly controlled lots of the vaccine in the national campaign. Since atypical B. melitensis biotype 1 strains have been characterized in Israel, the PCR technique has unequivocally demonstrated that strain Rev1 has not diverted into a virulent mutant. In addition, we could demonstrate that very likely a new prototype biotype 1 strain has evolved in the Middle East compared to the classical strain 16M. All the Israeli field strains have been shown to differ from strain 16M in the PstI digestion profile of the omp2a gene sequence suggesting that the local strains were possibly developed as a separate branch of B. melitensis. Should this be confirmed these data suggest that the Rev1 vaccine may not be an optimal vaccine strain for the Israeli flocks as it shares the same omp2 PstI digestion profile as strain 16M.