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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.
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Levings, Megan K., Romina Sangregorio, Claudia Sartirana, Anna Lisa Moschin, Manuela Battaglia, Paul C. Orban, and Maria-Grazia Roncarolo. "Human CD25+CD4+ T Suppressor Cell Clones Produce Transforming Growth Factor β, but not Interleukin 10, and Are Distinct from Type 1 T Regulatory Cells." Journal of Experimental Medicine 196, no. 10 (November 11, 2002): 1335–46. http://dx.doi.org/10.1084/jem.20021139.
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T regulatory (Tr) cells are essential for the induction of peripheral tolerance. Several types of Tr cells exist, including CD4+ T cells which express CD25 constitutively and suppress immune responses via direct cell-to-cell interactions, and type 1 T regulatory (Tr1) cells, which function via secretion of interleukin (IL)-10 and transforming growth factor (TGF)-β. The relationship between CD25+CD4+ T cells and Tr1 cells remains unclear. Here, we demonstrate at the clonal level that Tr1 and CD25+CD4+ T cells are two distinct subsets of regulatory cells with different cytokine production profiles. Furthermore, CD25−CD4+ T cells can be rendered anergic by IL-10 and differentiated into Tr1 cells in the absence of CD25+CD4+ T cells. Cloned human CD25+CD4+ T cell populations are heterogeneous and only a subset of clones continues to express high levels of CD25 and is suppressive. The intensity of CD25, cytotoxic T lymphocyte antigen (CTLA)-4, and glucocorticoid-induced tumor necrosis factor (TNF) receptor expression correlates with the suppressive capacity of the T cell clones. None of the CD25+CD4+ T cell clones with suppressive function produce IL-10, but all produce TGF-β. Suppression mediated by CD25+CD4+ T cell clones is partially dependent on TGF-β, but not on constitutive high expression of CD25. Together these data indicate that naturally occurring human CD25+CD4+ T cells are distinct from IL-10–producing Tr1 cells.
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Liu, Jeffrey M., Pauline Chen, Brandon Cieniewicz, Alma-Martina Cepika, Rosa Bacchetta, and Maria Grazia Roncarolo. "Engineered Type-1 Regulatory T Cells as Cellular Therapy for Treatment of Immune Mediated Diseases." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 87.17. http://dx.doi.org/10.4049/jimmunol.204.supp.87.17.
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Abstract Type 1 regulatory cells (Tr1) are a promising cellular product for suppression of effector T cells in immune mediated diseases, including graft-versus-host-disease (GvHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) (Roncarolo et al. Immunity 2018). We have developed an in vitro protocol to produce Tr1 cells by lentiviral transduction of the human IL10 with a constitutive promoter into human CD4+ T cells (Locafaro et al. Molecular Therapy 2017). These engineered Tr1 cells, called LV-10, acquire a characteristic Tr1 cytokine profile (IL-10 and IFN-g high, IL-4 low and expression of intracellular perforin and granzyme B). In vitro, LV-10 cells suppress the proliferation of responder CD4+ T cells upon activation by allogeneic dendritic cells. LV-10 cells also degranulate in response to and kill myeloid cells, including myeloid blasts from patients with acute myeloid leukemia, through a granzyme B- and perforin-dependent mechanism. Interestingly, the ability to degranulate and kill myeloid cells is not present when LV-10 are activated and expanded with anti-CD3 and anti-CD28 coated beads, suggesting that signals beyond TCR, CD28, and IL-10 receptor pathway activation are necessary to reprogram LV-10 cells into cytotoxic cells. In vivo, LV-10 cells injected into NSG mice do not induce xeno-GvHD, in contrast to control CD4+ T cells. In addition, LV-10 cells suppress CD4-induced xeno-GvHD and prevent expansion of myeloid leukemic cells. Experiments are ongoing to compare the potency and in vivo survival of allogeneic vs autologous LV-10 cells. These findings demonstrate the promise of using LV-10 to treat immune mediated diseases, including GvHD in AML patients receiving allo-HSCT.
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Huang, Weishan, Sabrina Solouki, Nicholas Koylass, Song-Guo Zheng, and Avery August. "ITK signaling via the Ras/IRF4 pathway regulates the development and function of type 1 regulatory T cells." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 52.8. http://dx.doi.org/10.4049/jimmunol.198.supp.52.8.
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Abstract Type 1 regulatory T (Tr1) cells differentiate in response to signals engaging T cell receptor (TCR), express high levels of the immunosuppressive cytokine IL-10 but not Foxp3, and can suppress inflammation and promote immune tolerance. Here, using IL-10GFP/Foxp3RFP dual reporter transgenic mouse system, we show that ITK, a key modulator of TCR signaling, is required for the development of Tr1 cells in various organs following TCR activation, and in the mucosal system during parasitic and viral infections. ITK kinase activity is required for mouse and human Tr1 cell fate programming and regulates the balance between IL-10 and IFN-γ production during Tr1 cell differentiation. The requirement for ITK function during Tr1 cell development and suppressive function can be restored by the expression of the transcription factor IRF4. Downstream of ITK, Ras, and MAP kinases ERK1/2, p38 and JNK, are required for Tr1 cell differentiation, but not Th17 cell differentiation. We have previously shown that Th17 differentiation is also dependent on ITK signaling. However, in the absence of ITK, expression of the constitutively active HRasG12V rescued IRF4 expression and Tr1 cell differentiation, but failed to restore Th17 cell differentiation. We conclude that the TCR/ITK signaling through the Ras/MAPK/IRF4 pathway is specifically required for functional development of Tr1 cells, and that targeting these signaling components may be of therapeutic benefit.
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Mari, Elisabeth, Javad Rasouli, Guang-Xian Zhang, Bogoljub Ciric, and A. Rostami. "Galectin-1 plays an essential role in intravenous tolerance in experimental autoimmune encephalomyelitis (BA4P.139)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 47.19. http://dx.doi.org/10.4049/jimmunol.194.supp.47.19.
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Abstract Multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory demyelinating diseases of the central nervous system (CNS). EAE can be induced by immunizing mice with myelin oligodendrocyte glycoprotein-derived peptide, MOG35-55, in adjuvant. It has been previously demonstrated that intravenous (i.v.) injection of MOG35-55 post immunization induction suppresses disease development, a phenomenon called i.v. tolerance. The glycan-binding protein galectin-1, produced primarily by regulatory T cells plays an immunoregulatory role in EAE by inducing tolerogenic DCs and IL-10-producing regulatory type 1 T cells (Tr1). To examine the role of galectin-1 in i.v. tolerance, we administered MOG35-55 peptide i.v. to wild-type (WT) and galectin-1-/- (Gal1-/-) mice with ongoing EAE. MOG35-55 rapidly suppressed disease in the WT, but not in the Gal1-/- mice. Expression of pro-inflammatory cytokines IFN-gamma and IL-17A were reduced in the CNS and periphery of tolerized WT mice, while the number of Tr1 cells increased in the periphery. In contrast, i.v. MOG35-55 significantly increased IFN-gamma and IL-17A in the CNS and periphery of Gal1-/-mice and these mice had markedly fewer Tr1 cells in the periphery. Our data suggest that galectin-1 mediated i.v. tolerance induction is dependent on the downregulation of Th1 and Th17 pro-inflammatory responses, and enhanced development of Tr1 cells.
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Meiler, Flurina, Judith Zumkehr, Sven Klunker, Beate Rückert, Cezmi A. Akdis, and Mübeccel Akdis. "In vivo switch to IL-10–secreting T regulatory cells in high dose allergen exposure." Journal of Experimental Medicine 205, no. 12 (November 10, 2008): 2887–98. http://dx.doi.org/10.1084/jem.20080193.
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High dose bee venom exposure in beekeepers by natural bee stings represents a model to understand mechanisms of T cell tolerance to allergens in healthy individuals. Continuous exposure of nonallergic beekeepers to high doses of bee venom antigens induces diminished T cell–related cutaneous late-phase swelling to bee stings in parallel with suppressed allergen-specific T cell proliferation and T helper type 1 (Th1) and Th2 cytokine secretion. After multiple bee stings, venom antigen–specific Th1 and Th2 cells show a switch toward interleukin (IL) 10–secreting type 1 T regulatory (Tr1) cells. T cell regulation continues as long as antigen exposure persists and returns to initial levels within 2 to 3 mo after bee stings. Histamine receptor 2 up-regulated on specific Th2 cells displays a dual effect by directly suppressing allergen-stimulated T cells and increasing IL-10 production. In addition, cytotoxic T lymphocyte–associated antigen 4 and programmed death 1 play roles in allergen-specific T cell suppression. In contrast to its role in mucosal allergen tolerance, transforming growth factor β does not seem to be an essential player in skin-related allergen tolerance. Thus, rapid switch and expansion of IL-10–producing Tr1 cells and the use of multiple suppressive factors represent essential mechanisms in immune tolerance to a high dose of allergens in nonallergic individuals.
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Ouaguia, Laurissa, Olivier Morales, Dhafer Mrizak, Khaldoun Ghazal, Emmanuel Boleslawski, Claude Auriault, Véronique Pancré, Yvan de Launoit, Filoména Conti, and Nadira Delhem. "Overexpression of Regulatory T Cells Type 1 (Tr1) Specific Markers in a Patient with HCV-Induced Hepatocellular Carcinoma." ISRN Hepatology 2013 (October 23, 2013): 1–7. http://dx.doi.org/10.1155/2013/928485.
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Hepatitis C virus (HCV) is an important causative agent of liver disease, but factors that determine the resolution or progression of infection are poorly understood. In this study, we suggested that existence of immunosuppressive mechanisms, supported by regulatory T cells and especially the regulatory T cell 1 subset (Tr1), may explain the impaired immune response during infection and thus the fibrosis aggravation to hepatocellular carcinoma (HCC). Using quantitative real-time PCR, we investigated the intra-hepatic presence of Tr1 cells in biopsies from a genotype 1b infected patient followed for an 18-year period from cirrhosis to HCC. We described a significant increase of gene expression in particular for the cytokines IL-10, TGF-β, and their receptors that were perfectly correlated with an increased expression of the Tr1 specific markers (combined expression of CD4, CD18, and CD49b). This was strongly marked since the patient evolved in the pathology and could explain the failure of the treatment. In conclusion, evidence of regulatory T cell installation in the liver of chronically infected patient with cirrhosis and HCC suggests for the first time a key role for these cells in the course of HCV infection.
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Wan, Jiangbo, Fang Huang, Siguo Hao, Weiwei Hu, Chuanxu Liu, Wenhao Zhang, Xiaohui Deng, Linjun Chen, Liyuan Ma, and Rong Tao. "Interleukin-10 Gene-Modified Dendritic Cell-Induced Type 1 Regulatory T Cells Induce Transplant-Tolerance and Impede Graft Versus Host Disease After Allogeneic Stem Cell Transplantation." Cellular Physiology and Biochemistry 43, no. 1 (2017): 353–66. http://dx.doi.org/10.1159/000480415.
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Background/Aims: Tr1 cells can induce peripheral tolerance to self- and foreign antigens, and have been developed as a therapeutic tool for the induction of tolerance to transplanted tissue. We explored the feasibility of generating Tr1 cells by using IL-10 gene-modified recipient DCs (DCLV-IL-10) to stimulate donor naive CD4+ T cells. We also investigated some biological properties of Tr1 cells. Methods: DCLV-IL-10 were generated through DCs transduced with a lentivirus vector carrying the IL-10 gene, and Tr1 cells were produced by using DCLV-IL-10 to stimulate naive CD4+ T cells. The effects of Tr1 cells on T-cell proliferation and the occurrence of graft versus host disease (GVHD) following allogeneic stem-cell transplantation (allo-HSCT) were investigated. Results: The DCLV-IL-10-induced Tr1 cells co-expressed LAG-3 and CD49b. Moreover, they also expressed CD4, CD25, and IL-10, but not Foxp3, and secreted significantly higher levels of IL-10 (1,729.36 ± 185.79 pg/mL; P < 0.001) and INF-γ (1,524.48 ± 168.65 pg/mL; P < 0.01) than the control T cells upon the stimulation by allogeneic DCs. Tr1 cells markedly suppressed T-lymphocyte proliferation and the mixed lymphocytic response (MLR) in vitro. The mice used in the allo-HSCT model had longer survival times and lower clinical and pathological GVHD scores than the control mice. Conclusion: IL-10 gene-modified DC-induced Tr1 cells may be used as a potent cellular therapy for the prevention of GVHD after allo-HSCT.
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Ma, Yanchun, Vera Bauer, Tanja Riedel, Thomas Hofer, Martin Roecken, and Ralph Mocikat. "837 Interleukin-10 drives the development of T regulatory type 1 (Tr1) cells and is a target for immunotherapy." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A889. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0837.
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BackgroundIn recent years, immunotherapy has become a common tool of cancer treatment. In order to define therapeutic targets, it is necessary to understand mechanisms of tumor-induced immunosuppression. In malignant B-cell lymphoma, the effects of the anti-inflammatory cytokine interleukin-10 (IL-10) remain poorly understood.MethodsTo investigate the role of IL-10 in a tumor microenvironment, we used λ-MYC-transgenic mice that spontaneously develop B-cell lymphoma. The experiments were performed either in vivo or in vitro and the cell samples were then analyzed by flow cytometry.ResultsIn MYC tumors, CD4+Foxp3- effector T cells maintained the expression of interferon-γ (IFN-γ), yet became exhausted. Within this population we found a cell fraction of unknown origin coexpressing IFN-γ and IL-10 that increased during disease progression. These cells turned out to be T regulatory type 1 (Tr1) cells, which are known to be immunosuppressive. When exposing homogeneous IFN-γ-producing T helper type 1 (Th1) cells to a MYC tumor milieu in vitro, part of these cells started to express both, IFN-γ and IL-10, and showed an increased level of programmed cell death protein 1 (PD-1). Notably, these changes diminished when an IL-10 neutralizing monoclonal antibody (mAb) was added to the coculture, indicating that IL-10 is necessary for the Tr1 development and is involved in the upregulation of PD-1. In line with these results, we treated λ-MYC mice with anti-IL-10 mAb. This therapy not only led to significantly prolonged survival but also decreased expression of PD-1 on effector T cells and increased proliferation of cytotoxic T cells.ConclusionsIn summary, these results showed the importance of IL-10 for the tumor immune escape in lymphoma. IL-10 induced a conversion from Th1 to Tr1 cells and elevated levels of PD-1. Both effects were diminished after IL-10 ablation. Thus, targeting IL-10 might be a promising new approach of immunotherapy.Ethics ApprovalAll animal studies were approved by Regierung von Oberbayern, approval number 55.2-1-54.
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Lisko, D., S. Menzies, L. M. Sly, and T. Steiner. "A10 TR1 CELL-BASED THERAPY FOR INFLAMMATORY ILEITIS IN SHIP-/- MICE." Journal of the Canadian Association of Gastroenterology 3, Supplement_1 (February 2020): 12–13. http://dx.doi.org/10.1093/jcag/gwz047.009.
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Abstract Background Crohn’s disease (CD), a form of inflammatory bowel disease (IBD), is characterized by chronic inflammation that can occur anywhere along the gastrointestinal (GI) tract, but commonly involves the distal portion of the ileum. Src homology 2 (SH2) domain-containing inositol polyphosphate 5-phosphatase 1 (SHIP) is a hematopoietic-specific regulator of secondary signals generated by the PI3K pathway and regulates immune activation. SHIP-/- mice, at 6–8 weeks of age, spontaneously develop inflammatory ileitis due to myeloid proliferation, a lack of T cells, and an increase in IL-1β. Aims Here we investigated the efficacy of type 1 regulatory T (Tr1) cells, which are characterized by high IL-10 production, a broadly acting anti-inflammatory cytokine that promotes gut homeostasis, to treat ileitis in SHIP-/- mice. Methods Using IL-10GFPFOXP3RFP B6 reporter mice, we sorted FOXP3-CD44High Tr1 cells, FOXP3+ Tregs, and FOXP3-CD44Low naive T cells from total CD4+ T cells, and cultured them with immobilized α-CD3, soluble α-CD28 and recombinant IL-2 for 3 days. Naive T cells were grown in undifferentiated conditions or polarized to Th1 or Th17 cells. Cell phenotypes were characterized by ELISA and flow cytometry. For the adoptive Tr1 cell transfer, CD44High cells were sorted from FOXP3GFP Thy1.1 reporter mice and cultured as above with an additional 2 days’ rest in the presence of IL-2 alone. SHIP-/- mice and wild type (WT) littermates were sublethally irradiated at 5 weeks of age, followed 24h later by IP injection with 0.7 – 1.0 x 106 Tr1 cells or PBS vehicle. At 7 weeks of age, mice were euthanized and blood, mesenteric lymph nodes (MLNs), and ileal tissue were processed. Results After 3 days of stimulation, FOXP3-CD44High Tr1 cells produced more IL-10 than Tregs and less IFN-γ than Th1 cells. Additionally, CD44High cells had higher co-expression of CD49b and Lag3, biomarkers for Tr1 cells, in comparison to nT cells, Tregs, Th1, and Th17 cells, a higher percentages of IL-10 producing cells than FOXP3+ Tregs and produced less IFN-γ, IL-17, and TNF-α in comparison to Th1, Th17 and naive T cells, respectively. We found that Tr1 cells successfully engrafted irradiated SHIP-/- mice. Furthermore, engrafted Tr1 cells had high co-expression of CD49b and Lag3, with the majority of these cells located in the MLNs and spleen. SHIP KO mice that received Tr1 cells had comparable ileal length and appearance to SHIP WT, and significantly longer ilea versus SHIP PBS controls — indicating decreased inflammation as a result of successful engraftment. Conclusions In conclusion, ex-vivo expansion and adoptive transfer of Tr1 cells to SHIP-/- mice led to cellular engraftment and improvement in spontaneous ileitis. Hence, Tr1 cellular therapy shows promise as a therapeutic approach in CD. Future experiments will be needed to determine the therapeutic dose range of Tr1 cells and the mechanisms of protection. Funding Agencies CCC
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Karwacz, Katarzyna, Nir Yosef, and Vijay Kuchroo. "IRF-1 is a key transcriptional regulator of Tr1 differentiation (P1135)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 50.10. http://dx.doi.org/10.4049/jimmunol.190.supp.50.10.
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Abstract IL-10 producing Type 1 regulatory T cells (Tr1) are crucial for maintenance of peripheral tolerance and prevention of autoimmune inflammation. Using IL-27 as the differentiation factor, we undertook a detailed whole genome transcriptional network analysis of differentiating Tr1 cells. We identified IRF-1 as a key transcriptional regulator of Tr1 differentiation. Our studies demonstrate a critical requirement for IRF1 in the generation of Tr1 cells both in vitro and in vivo. IRF1-/- mice immunized for the development of Experimental autoimmune encephalomyelitis (EAE) develop very severe clinical disease and fail to recover. Furthermore, CD4+ T cells in IRF1-deficient mice with active disease showed increased number of IL-17 secreting cells in the CNS. In fact, over-expression of IRF1 during Th17 differentiation suppresses induction of both IL17 and IL23 receptor, the role opposite to the one played by another IRF family member - IRF4. Interestingly, loss of IRF-1 enhances IRF4 binding to the key DNA-binding sites involved in Th17 differentiation and functional assays further support that IRF1 can actively repress IRF4-mediated transactivation of IL17A, pointing to a cross-competition of IRF1 and IRF4 for the same DNA-binding sites in CD4+ T cells. Collectively these data demonstrate a critical role of IRF-1 in the generation of Tr1 cells, but at the same time, the induction of IRF-1 represses Th17 differentiation by actively inhibiting IRF-4 mediated Th17 differentiation.
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Häringer, Barbara, Laura Lozza, Bodo Steckel, and Jens Geginat. "Identification and characterization of IL-10/IFN-γ–producing effector-like T cells with regulatory function in human blood." Journal of Experimental Medicine 206, no. 5 (May 4, 2009): 1009–17. http://dx.doi.org/10.1084/jem.20082238.
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Two subsets of natural and adaptive regulatory T (T reg) cells have been described, but the identity of adaptive type 1 regulatory (Tr1)–like cells in humans is unclear. We analyzed a subset of human blood CD4+ T cells—CD45RA−CD25−interleukin (IL)-7 receptor (R)− cells—that rapidly secreted high levels of IL-10 together with interferon γ, but produced little IL-2. These IL-7R− T cells were rare, anergic, and largely Foxp3−. They expressed low levels of Bcl-2 but high levels of Ki-67 and ICOS, suggesting that they have been recently activated in vivo. Consistently, they responded selectively to persistent foreign and self-antigens under steady-state conditions. Unlike natural CD25+ T reg cells, IL-7R− cells suppressed naive and memory T cell proliferation in an IL-10–dependent fashion, and they required strong T cell receptor stimulation for suppression. To our knowledge, this is the first report that identifies Tr1-like cells in human blood. These IL-10–secreting cells have characteristics of chronically activated Th1 effector cells and are distinct from CD25+ T reg cells.
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Gregori, Silvia, Daniela Tomasoni, Valentina Pacciani, Miriam Scirpoli, Manuela Battaglia, Chiara Francesca Magnani, Ehud Hauben, and Maria-Grazia Roncarolo. "Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10–dependent ILT4/HLA-G pathway." Blood 116, no. 6 (August 12, 2010): 935–44. http://dx.doi.org/10.1182/blood-2009-07-234872.
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Abstract Type 1 T regulatory (Tr1) cells suppress immune responses in vivo and in vitro and play a key role in maintaining tolerance to self- and non–self-antigens. Interleukin-10 (IL-10) is the crucial driving factor for Tr1 cell differentiation, but the molecular mechanisms underlying this induction remain unknown. We identified and characterized a subset of IL-10–producing human dendritic cells (DCs), termed DC-10, which are present in vivo and can be induced in vitro in the presence of IL-10. DC-10 are CD14+, CD16+, CD11c+, CD11b+, HLA-DR+, CD83+, CD1a−, CD1c−, express the Ig-like transcripts (ILTs) ILT2, ILT3, ILT4, and HLA-G antigen, display high levels of CD40 and CD86, and up-regulate CD80 after differentiation in vitro. DC-10 isolated from peripheral blood or generated in vitro are potent inducers of antigen-specific IL-10–producing Tr1 cells. Induction of Tr1 cells by DC-10 is IL-10–dependent and requires the ILT4/HLA-G signaling pathway. Our data indicate that DC-10 represents a novel subset of tolerogenic DCs, which secrete high levels of IL-10, express ILT4 and HLA-G, and have the specific function to induce Tr1 cells.
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Cepika, Alma-Martina, Pauline P. Chen, Molly Uyeda, Brandon Cieniewicz, Mansi Narula, Laura Amaya, David M. Louis, et al. "146 Alloantigen-specific Tr1 cells designed to prevent GvHD have a distinct molecular identity and suppress through CTLA-4 and PD-1." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A159. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0146.
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BackgroundGraft-vs-host-disease (GvHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), limiting the use of this potentially curative treatment for hematological malignancies. To address this, we have developed T-allo10 cell therapy, which is enriched with type 1 regulatory T (Tr1) cells. Tr1 cells are peripherally inducible, CD49b+LAG3+IL-10+FOXP3- regulatory T cells that can confer alloantigen-specific tolerance, making them an attractive alternative to existing GvHD therapies, which non-discriminately impair both GvHD and protective immunity. T-allo10 cells are currently being evaluated in a phase I clinical trial in patients with hematological malignancies undergoing allo-HSCT (NCT03198234). Herein, we aimed to confirm that Tr1 cells are the active ingredient responsible for the T-allo10 suppressive function, and reveal the underlying molecular signatures to elucidate the mechanisms of Tr1 cell-mediated suppression.MethodsT-allo10 cells were generated in a co-culture of healthy host or patient tolerogenic dendritic cells (DC-10) with allogeneic healthy donor CD4+ T cells, then tested for Tr1 phenotype, anergy, suppression and cytokine production. Sorted T-allo10-derived Tr1 cells and non-Tr1 cells, as well as control effector T cells (Teff) and parental CD4+ T cells, were analyzed by TCR- and RNA-seq. Protein expression for key differentially expressed genes were validated, and the functional roles for IL-10, CTLA-4 and PD-1 in T-allo10-mediated suppression were confirmed in a suppression assay.ResultsWe show that the T-allo10 cell product is: i) enriched for Tr1 cells, ii) anergic in response to alloantigen re-challenge, but not to non-specific stimuli or 3rd party antigens, and iii) suppresses host-reactive T cells, but not T cell responses to other antigens. Furthermore, T-allo10-derived, isolated Tr1 cells had a restricted TCR repertoire, suggesting they clonally expand in response to alloantigens. T-allo10-derived Tr1 cells have a distinct signature compared to non-Tr1 cells, and, in addition to IL-10, express high levels of CTLA-4 and PD-1 (but not FOXP3). Notably, blockade of CTLA-4 and the PD-1 pathway completely abolishes T-allo10-mediated suppression of T cell responses.ConclusionsOur data shows that Tr1 cells are the active, suppressive, and antigen-specific ingredient of T-allo10 cells. Furthermore, while the role of IL-10 in Tr1 cell-mediated suppression is well known, we uncover that Tr1 suppress in addition through CTLA-4 and PD-1. Collectively, these intriguing findings underscore the importance of CTLA-4 and PD-1 pathways in conferring cell-mediated immunological tolerance. Further, they define the key characteristics and modes of action of antigen-specific Tr1 cells, providing crucial information for the ongoing T-all10 trial and future design of novel Tr1 cell-based therapies.Ethics ApprovalThe patient study was approved by Administrative Panels on Human Subjects in Medical Research, Stanford University, Tallo10 eProtocol # 38734. Healthy donor samples were purchased as deidentified human blood products from the Stanford Blood Center, and are thus exempt.
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Mfarrej, B., T. Jofra, C. Morsiani, N. Gagliani, G. Fousteri, and M. Battaglia. "Key role of macrophages in tolerance induction via T regulatory type 1 (Tr1) cells." Clinical & Experimental Immunology 201, no. 2 (May 13, 2020): 222–30. http://dx.doi.org/10.1111/cei.13440.
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Matsuda, Masaya, Tetsuya Terada, Miki Inaba, Junpei Hamaguchi, Naoki Takemoto, Kazuyuki Kitatani, Ryo Kawata, and Takeshi Nabe. "Type 1 regulatory T (Tr1) cells increased by sublingual immunotherapy (SLIT) suppressed allergic inflammation." Proceedings for Annual Meeting of The Japanese Pharmacological Society 93 (2020): 1—O—002. http://dx.doi.org/10.1254/jpssuppl.93.0_1-o-002.
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Chen, Xiaoting, Hongwen Ma, Lina Gong, Guang Yang, and Xi Jin. "Porcine-Stimulated Human Tr1 Cells Showed Enhanced Suppression in Xenoantigen Stimulation Response." Computational and Mathematical Methods in Medicine 2021 (November 8, 2021): 1–11. http://dx.doi.org/10.1155/2021/2725799.
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Type 1 regulatory T (Tr1) cells play a fundamental role in maintaining and inducing immune tolerance. Our preliminary study demonstrated that an interleukin- (IL-) 10-mediated pathway is a possible regulatory mechanism underlying the xenoantigen-specific human Treg enhanced suppressive capacity. Here, we developed a feasible protocol for expanding IL-10-induced xenoantigen-specific human Tr1 cells in vitro which would be more efficient in transplantation immunotherapy efficiency. In this study, xenoantigen-specific Tr1 cells are generated from human naive CD4+ T cells expanded for two subsequent xenoantigen-stimulation cycles with recombinant human IL-10. The phenotype and suppressive capacity of xenoantigen-stimulated Tr1 cells are assessed, and the mechanism of their suppression is studied. Tr1 cells can be induced by porcine xenoantigen stimulation combined with IL-10, IL-2, and IL-15, displaying an increased expression of CD49b, CTLA-4, and LAG-3 without expressing Foxp3 which also showed an effector memory Treg phenotype and expressed high levels of CD39. After xenoantigen stimulation, the IL-10 and IL-5 gene expression in Tr1 cells increased, secreting more IL-10, and xenoantigen-stimulated Tr1 cells changed their T cell receptor (TCR) Vβ repertoire, increasing the expression of TCR Vβ2, TCR Vβ9, and TCR Vβ13. In a pig to human mixed lymphocyte reaction (MLR), xenoantigen-stimulated Tr1 cells displayed enhanced suppressive capacity via CD39 in a dose-dependent manner. Moreover, IL-5 could affect the proliferation of xenoantigen-specific Tr1 cells, but not their phenotypes’ expression. This study provides a theory and feasible method for immune tolerance induction in clinical xenotransplantation.
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Zhang, Huiyuan, Asaf Madi, Nir Yosef, Norio Chihara, Amit Awasthi, Caroline Pot, Lionel Apetoh, et al. "Transcriptional regulation of IL-10 in T helper cells." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 124.14. http://dx.doi.org/10.4049/jimmunol.202.supp.124.14.
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Abstract IL-10 produced by CD4 T cells plays an essential role in limiting inflammation and autoimmunity. All T help cell subsets can co-produce IL-10 to mitigate unwanted immunopathology but naïve CD4 T cells can also be directly polarized to IL-10 producing Type 1 regulatory (Tr1) cells by the immunoregulatory cytokine, IL-27. Although several transcription factors (TFs) have been shown to regulate IL-10 expression in different contexts, a comprehensive transcriptional network that induce and maintain IL-10 in various CD4 T cells is lacking. Here we utilized two complementary approaches to systemically study the transcriptional mechanisms driving IL-10 production in T helper cells: 1) We combined novel computational tools with transcriptomic profiling of in-vitro Tr1 cell differentiation at high temporal resolution to build a comprehensive and dynamic transcriptional network that regulates IL-10 production in CD4 T cells. We identified four transcription waves that govern Tr1 differentiation: dynamic early phase, stable early phase, induction phase and maintenance phase. Based on the network analysis, we computationally predicted 78 TFs that regulate different waves and experimentally validated 24 of them using knock-out mice. 2) To identify TFs associated with IL-10 production across T helper cell subsets, we compared RNA-seq data of IL-10+ versus IL-10− compartments of in-vitro differentiated Th1, Th2 and Th17 cells. Using a comprehensive ranking scheme, we identified two TFs that regulates IL-10 production in all helper T cell subsets. Conditional deletion of both the TFs but not either alone with CD4-Cre abolishes IL-10 production from Tr1 cells in vitro and leads to spontaneous colitis in vivo.
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Elmore, Jessica P., Michael C. McGee, Natalie F. Nidetz, Orchi Anannya, Weishan Huang, and Avery August. "Tuning T helper cell differentiation by ITK." Biochemical Society Transactions 48, no. 1 (February 12, 2020): 179–85. http://dx.doi.org/10.1042/bst20190486.
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CD4+ effector T cells effectuate T cell immune responses, producing cytokines to orchestrate the nature and type of immune responses. The non-receptor tyrosine kinase IL-2 inducible T cell kinase (ITK), a mediator of T cell Receptor signaling, plays a critical role in tuning the development of these effector cells. In this review we discussed the role that signals downstream of ITK, including the Ras/MAPK pathway, play in differentially controlling the differentiation of TH17, Foxp3+ T regulatory (Treg) cells, and Type 1 regulatory T (Tr1) cells, supporting a model of ITK signals controlling a decision point in the effector T cell differentiation process.
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Levings, Megan K., Silvia Gregori, Eleonora Tresoldi, Sabrina Cazzaniga, Chiara Bonini, and Maria Grazia Roncarolo. "Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Tr cells." Blood 105, no. 3 (February 1, 2005): 1162–69. http://dx.doi.org/10.1182/blood-2004-03-1211.
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Abstract Dendritic cells (DCs) are specialized antigen-presenting cells that monitor the antigenic environment and activate naive T cells. The role of DCs is not only to sense danger but also to tolerize the immune system to antigens encountered in the absence of maturation/inflammatory stimuli. Indeed, if a naive T cell encounters its antigen on immature DCs (iDCs), it may differentiate into a T-regulatory (Tr) rather than a T-effector cell. However, little is known about the mechanisms by which iDCs differentiate Tr cells. We developed a standardized and highly reproducible protocol to differentiate Tr cells by repetitive exposure of naive peripheral blood CD4+ T cells to allogeneic iDCs. The resultant Tr cells are phenotypically and functionally identical to type 1 Tr (Tr1) cells because their generation requires production of IL-10 by iDCs, and they suppress T-cell responses through an interleukin-10 (IL-10)– and a transforming growth factor β (TGF-β)–dependent mechanism. In addition, Tr1 cells induced by iDCs do not require the presence of CD4+CD25+ Tr cells for their generation, nor do they express high constitutive levels of CD25 or the transcription factor FoxP3. Thus, iDCs can drive the differentiation of Tr1 cells and can be used to generate large numbers of alloantigen-specific Tr1 cells for clinical use as a cellular therapy to restore peripheral tolerance.
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Guo, H., R. Han, F. Zhou, and C. Zhou. "50P T regulatory type 1 (Tr1) cells, a potential target in EGFR TKI-resistant NSCLC." Annals of Oncology 33 (September 2022): S562. http://dx.doi.org/10.1016/j.annonc.2022.07.077.
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Asemissen, A., U. Keilholz, M. Guerreiro, S. Bauer, I. Na, A. Letsch, E. Thiel, J. Huehn, and C. Scheibenbogen. "IL-2 treatment decreases frequencies of IL-10-producing regulatory T cells type 1 (Tr1)." Melanoma Research 16, Supplement 1 (September 2006): S32. http://dx.doi.org/10.1097/00008390-200609001-00055.
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Truscott, Steven M., Getahun Abate, Jeffrey D. Price, Claudia Kemper, John P. Atkinson, and Daniel F. Hoft. "CD46 Engagement on Human CD4+ T Cells Produces T Regulatory Type 1-Like Regulation of Antimycobacterial T Cell Responses." Infection and Immunity 78, no. 12 (October 4, 2010): 5295–306. http://dx.doi.org/10.1128/iai.00513-10.
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ABSTRACT Understanding the regulation of human immune responses is critical for vaccine development and treating infectious diseases. We have previously shown that simultaneous engagement of the T cell receptor (TCR) and complement regulator CD46 on human CD4+ T cells in the presence of interleukin-2 (IL-2) induces potent secretion of the immunomodulatory cytokine IL-10. These T cells mediate IL-10-dependent suppression of bystander CD4+ T cells activated in vitro with anti-CD3 and anti-CD28 costimulation, reflecting a T regulatory type 1 (Tr1)-like phenotype. However, CD46-mediated negative regulation of pathogen-specific T cells has not been described. Therefore, we studied the ability of CD46-activated human CD4+ T cells to suppress T cell responses to Mycobacterium bovis BCG, the live vaccine that provides infants protection against the major human pathogen Mycobacterium tuberculosis. Our results demonstrate that soluble factors secreted by CD46-activated human CD4+ T cells suppress mycobacterium-specific CD4+, CD8+, and γ9δ2 TCR+ T cells. Dendritic cell functions were not downregulated in our experiments, indicating that CD46-triggered factors directly suppress pathogen-specific T cells. Interestingly, IL-10 appeared to play a less pronounced role in our system, especially in the suppression of γ9δ2 TCR+ T cells, suggesting the presence of additional undiscovered soluble immunoregulatory factors. Blocking endogenous CD46 signaling 3 days after mycobacterial infection enhanced BCG-specific T cell responses in a subset of volunteers. Taken together, these results indicate that CD46-dependent negative regulatory mechanisms can impair T cell responses vital for immune defense against mycobacteria. Therefore, modulating CD46-induced immune regulation could be integral to the development of improved tuberculosis therapeutics or vaccines.
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Roncarolo, Maria Grazia, Manuela Battaglia, Rosa Bacchetta, Megan Levings, and Silvia Gregori. "T-Cell-Mediated Suppression: From Bench to Bedside." Blood 122, no. 21 (November 15, 2013): SCI—37—SCI—37. http://dx.doi.org/10.1182/blood.v122.21.sci-37.sci-37.
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Abstract T regulatory cells (Tregs) play a pivotal role in promoting and maintaining tolerance. Several subsets of Tregs have been identified but, to date, the best characterized are the CD4+FOXP3+ Tregs (FOXP3+Tregs), thymic-derived or induced in the periphery, and the CD4+ IL-10-producing T regulatory type 1 (Tr1) cells. In the past decade much effort has been dedicated to develop methods for the in vitro induction and expansion of FOXP3+Tregs and of Tr1 cells for Treg-based cell therapy to promote and restore tolerance in T-cell mediated diseases, and for expanding antigen (Ag)-specific Tregs in vivo. FOXP3+Tregs constitutively express high levels of CD25 and of the transcription factor FOXP3. FOXP3+Tregs are distinguished from activated CD4+ T cells by the low expression of CD127, and by the DNA demethylation of a specific region of the FOXP3 gene called Treg-specific demethylated region (TSDR). FOXP3+Tregs suppress effector T-cell responses through cell-to-cell contact-dependent mechanisms and suppression requires activation via TCR and is IL-2 dependent. In vitro protocols to expand FOXP3+Tregs for adoptive transfer in vivo have been established. We demonstrated that rapamycin permits the in vitro expansion of FOXP3+Tregs while impairing the proliferation of non-Tregs. Moreover, rapamycin-expanded FOXP3+Tregs maintain their regulatory phenotype in a proinflammatory environment and Th17 cells do not expand in the presence of rapamycin. Despite the progress in FOXP3+Tregs expansion protocols, adoptive transfer of FOXP3+Tregs in humans remains a difficult experimental procedure due to the ability to expand a sufficient number of Ag-specific FOXP3+Tregs in vitro. To propagate a homogenous population of FOXP3+Tregs we developed a lentiviral vector (LV)-based strategy to ectopically express FOXP3 in CD4+ T cells. This method results in the development of suppressive cells that are super-imposable to FOXP3+Tregs. Conversion of effector T cells into FOXP3+Tregs upon LV-mediated gene transfer of wild-type FOXP3 was also obtained in CD4+T cells from immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) patients. We also developed a LV platform, which selectively targets expression of the transgene in hepatocytes, to induce tolerance to self or exogenous Ags. Using this approach we showed that systemic administration of LV encoding for the gene of interest leads to the induction of Ag-specific FOXP3+ Tregs, which mediate tolerance even in pre-immunized hosts. Tr1 cells are identified by their cytokine profile (IL-10+TGF-b+IL-4-IL-17-). Tr1 cells express transiently FOXP3 upon activation; but FOXP3 expression never reaches the high levels characteristic of FOXP3+Tregs. Tr1 cell differentiation and function is independent of FOXP3 since suppressive Tr1 cells can be isolated or generated from peripheral blood of IPEX patients. Tr1 cells were first discovered in peripheral blood of patients who developed tolerance after HLA-mismatched fetal liver hematopoietic stem cell transplant (HSCT). Since their discovery, Tr1 cells have proven to be important in mediating tolerance in several immune-mediated diseases. The immuno-regulatory mechanisms of Tr1 cells have been studied over the years thanks to the possibility to generate these cells in vitro. Tr1 cells suppress T-cell responses via the secretion of IL-10 and TGF-β and by the specific killing of myeloid APC via Granzyme B and perforin. Tr1 cells can be induced in vitro in an Ag-specific manner in the presence of IL-10 or of DC-10. Proof-of-principle clinical trials in allogeneic HSCT demonstrated the safety of Treg-based cell therapy with these polarized Tr1 cells. We are currently planning a phase I/II trial using in vitro polarized Tr1 cells with DC-10 in patients after kidney transplantation. An alternative strategy for the induction of high numbers of human Tr1 cells is the LV-mediated gene transfer of human IL-10 into conventional CD4+ T cells. Stable ectopic expression of IL-10 leads to the differentiation of homogeneous populations of Tr1-like cells displaying potent suppressive functions both in vitro and in vivo. A major hurdle, which limited the studies and the clinical use of Tr1 cells, was the lack of specific biomarkers. By gene expression profiling of human Tr1 cell clones we identified two surface markers (CD49b and LAG-3), which are stably and selectively co-expressed on murine and human Tr1 cells induced in vitro or in vivo. The co-expression of CD49b and LAG-3 enables the isolation of highly suppressive Tr1 cells from in vitro IL-10-polarized Tr1 cells and allows tracking of Tr1 cells in peripheral blood of patients who developed tolerance after allogeneic HSCT. The identification of CD49b and LAG-3 as Tr1-specific biomarkers will facilitate the study of Tr1 cells in vivo in healthy and pathological conditions and the use of Tr1 cells for forthcoming therapeutic interventions. In conclusion, Tregs play a key role in maintaining immunological homeostasis in the periphery. Several open questions regarding FOXP3+ Tregs or Tr1 cell-based therapy in humans remain: how long do Tregs survive after transfer? Is their phenotype stable in pathological conditions and inflammatory environments? Is their mechanism of suppression in vivo Ag-specific? Carefully designed and standardized future clinical protocols reflecting a concerted action among different investigators will help to address these questions and to advance the field. Disclosures: No relevant conflicts of interest to declare.
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Hooper, Kirsten M., Jui-Hung Yen, Weimin Kong, and Doina Ganea. "PGE2 and IL-27: novel pro-inflammatory mechanisms involving dendritic cells and Tr1 cells." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 189.9. http://dx.doi.org/10.4049/jimmunol.196.supp.189.9.
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Abstract 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 the inhibition of Th17 cell development and the induction of type 1 regulatory T cells (Tr1) and exhausted CD4+ T cells. The anti-inflammatory effects of IL-27 have been demonstrated in vivo in murine models of parasitic infections and autoimmune disease models such as experimental autoimmune encephalomyelitis and inflammatory bowel disease (IBD). We previously detailed the pro-inflammatory effects of PGE2 in collagen-induced arthritis and IBD through stimulation of IL-23 production leading to development of Th17 cells. Here we describe novel pro-inflammatory functions of PGE2, i.e. inhibition of IL-27 production by murine bone marrow-derived dendritic cells (DC), inhibition of Tr1 differentiation and of IL-10 production by Tr1 cells. We determined that the effect of PGE2 on IL-27 production in LPS-stimulated DC is mediated through EP2/EP4 receptors, induction of cAMP, and partial inhibition of both IRF1 and IRF3. Furthermore, we found that PGE2 treatment of LPS-stimulated DC reduces IRF1 binding to an essential ISRE site within the p28 promoter. In addition to the effects of IL-27 in DC, we also found that PGE2 directly inhibits IL-27-induced differentiation of Tr1 cells through EP4, and inhibits production of IL-10 by Tr1 cells through EP2/EP4. These studies further describe the pro-inflammatory effects of PGE2 and identify possible new targets for treatment of inflammatory diseases.
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Riley, John Samuel, Lauren Elizabeth McClain, Grace Lee, Haiying Li, Alan W. Flake, and William H. Peranteau. "In Utero Hematopoietic Cell Transplantation Induces Peripheral Tolerance By Upregulating Two Types of Nontraditional Regulatory T Cells." Blood 126, no. 23 (December 3, 2015): 5413. http://dx.doi.org/10.1182/blood.v126.23.5413.5413.
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Abstract Background: In utero hematopoietic cell transplantation (IUHCT) results in long-term, multilineage chimerism across immune barriers without myeloablation/immunosuppression. It has the potential to induce donor specific tolerance (DST) for postnatal nonmyeloablative cellular transplants to treat target diseases such as Sickle cell disease. Partial deletion of donor reactive host T cells and host reactive donor T cells is responsible for tolerance and the absence of GVHD following IUHCT. The remaining nondeleted donor and host specific T cells are thought to undergo anergy. The mechanisms by which anergy and peripheral tolerance are achieved following IUHCT are not completely understood. Studies in both mice and humans have demonstrated the importance of regulatory T cells in maintaining tolerance following postnatal allogeneic transplantation. Subsets of regulatory T cells include traditional regulatory T cells (Tregs; CD4+ CD25+ FoxP3+), Type 1 regulatory T cells (Tr1 cells; CD4+ CD49b+ CD223+), and LAP+ regulatory T cells (LAP+ cells; CD4+ CD25- LAP+). These T regulatory populations inhibit T cell activation and proliferation through, among other mechanisms, the secretion of immunosuppressive cytokines including IL-10. During pregnancy, there is upregulation of circulating IL-10 levels in maternal and fetal blood, and maternal antigen specific fetal Tregs are induced in peripheral lymphoid tissue. We propose that IUHCT takes advantage of these tolerogenic features of the fetus to promote the peripheral induction of regulatory T cells capable of suppressing reactive T cell clones that escape thymic deletion. Methods: 10x106 bone marrow cells from 6-8 week old C57Bl/6 (B6) FoxP3GFP (H2Kb) mice were injected intravenously into allogeneic gestational day 14 Balb/c FoxP3GFP fetal recipients (H2Kd). Uninjected B6 FoxP3GFP and Balb/c FoxP3GFP mice served as controls. Mice were sacrificed at 2 and 4 weeks of age. Peripheral blood donor chimerism was determined by flow cytometry at the time of sacrifice. Splenocytes were analyzed for expression of CD4, H2Kb, H2Kd, CD49b, CD223, CD25, and LAP to determine the percentage of donor and host Tregs, Tr1 cells, and LAP+ cells within the CD4+ population. CD4+ splenocytes were also assessed for intracellular IL-10 expression. Statistically significant differences between chimeric and uninjected control animals were determined using a two-tailed student's t-test. Results: Chimeric animals demonstrated a 4- and 5-fold increase in donor Tr1 cells compared to uninjected B6 FoxP3GFP controls at 2 (2.4% vs. 0.6%, p=0.03) and 4 weeks of age (2.4% vs. 0.5%, p=0.007). There was no significant difference in host Tr1 cell levels of chimeric mice compared to uninjected Balb/c FoxP3GFP controls at either 2 (0.73% vs. 0.61%, p=0.4) or 4 weeks of age (1.0% vs. 0.53%, p=0.09). Similar to Tr1 cells, LAP+ cells of donor origin were increased compared to B6 FoxP3GFP controls at 2 (2.2% vs. 0.8%, p=0.008) and 4 weeks of age (3.2% vs. 0.6%, p=0.03). Additionally, host LAP+ cells were increased compared to Balb/c FoxP3GFP controls at 2 (2.6% vs. 1.5%, p=0.0004) and 4 weeks of age (3.0% vs. 1.1%, p=0.0005). The increase in Tr1 and LAP+ cells was associated with a significant decrease in traditional Tregs in both the host and donor population at 2 and 4 weeks of age (Figure 1). Elevated levels of Tr1 and LAP+ cells did not correlate with the absolute levels of donor cell engraftment but was dependent on achieving a threshold level of chimerism known to be associated with DST. Furthermore, the MFI of intracellular IL-10 among donor CD4+ splenocytes was significantly increased compared to those from B6 FoxP3 controls at 2 weeks of age (Figure 2), demonstrating immunosuppressive activity consistent with elevated Tr1 and LAP+ levels. Conclusion: The induction of donor and host tolerance following IUHCT is important for maintaining successful long-term engraftment and preventing GVHD. DST also allows for postnatal nonmyeloablative cellular transplants to increase engraftment to therapeutically relevant levels. We demonstrate a potentially important role that nontraditional Tr1 and LAP+ regulatory T cells play in maintaining donor cell engraftment and peripheral tolerance in the setting of IUHCT. Future investigations into the ability of these cells to augment tolerance induction after inefficient IUHCT have the potential to expand the clinical promise of IUHCT. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.
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Tousa, Sofia, Maria Semitekolou, Ioannis Morianos, Aggelos Banos, Aikaterini I. Trochoutsou, Tess M. Brodie, Nikolaos Poulos, et al. "Activin-A co-opts IRF4 and AhR signaling to induce human regulatory T cells that restrain asthmatic responses." Proceedings of the National Academy of Sciences 114, no. 14 (March 20, 2017): E2891—E2900. http://dx.doi.org/10.1073/pnas.1616942114.
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Type 1 regulatory T (Tr1) cells play a pivotal role in restraining human T-cell responses toward environmental allergens and protecting against allergic diseases. Still, the precise molecular cues that underlie their transcriptional and functional specification remain elusive. Here, we show that the cytokine activin-A instructs the generation of CD4+ T cells that express the Tr1-cell–associated molecules IL-10, inducible T-Cell costimulator (ICOS), lymphocyte activation gene 3 protein (LAG-3), and CD49b, and exert strongly suppressive functions toward allergic responses induced by naive and in vivo-primed human T helper 2 cells. Moreover, mechanistic studies reveal that activin-A signaling induces the activation of the transcription factor interferon regulatory factor (IRF4), which, along with the environmental sensor aryl hydrocarbon receptor, forms a multipartite transcriptional complex that binds in IL-10 and ICOS promoter elements and controls gene expression in human CD4+ T cells. In fact, IRF4 silencing abrogates activin-A–driven IL10 and ICOS up-regulation and impairs the suppressive functions of human activin-A–induced Tr1-like (act-A–iTr1) cells. Importantly, using a humanized mouse model of allergic asthma, we demonstrate that adoptive transfer of human act-A–iTr1 cells, both in preventive and therapeutic protocols, confers significant protection against cardinal asthma manifestations, including pulmonary inflammation. Overall, our findings uncover an activin-A–induced IRF4-aryl hydrocarbon receptor (AhR)–dependent transcriptional network, which generates suppressive human Tr1 cells that may be harnessed for the control of allergic diseases.
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Caielli, Simone, Jacques Banchereau, and Virginia Pascual. "Dissecting the mechanisms responsible for the generation of regulatory versus pathogenic human CD4+ T cells by TLR9-activated plasmacytoid dendritic cells." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 230.3. http://dx.doi.org/10.4049/jimmunol.204.supp.230.3.
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Abstract Understanding the mechanisms underlying how regulatory and pathogenic CD4+ T cells are generated will accelerate therapeutic target identification in autoimmune diseases such as Systemic Lupus Erythematosus (SLE), where this balance is altered. We recently described that in vitro priming of naïve CD4+ T cells with plasmacytoid DCs (pDCs) activated with either CpGA or Oxidized mitochondrial DNA (Ox mtDNA) leads to the generation of Type 1 regulatory T cells (Tr1) or of a novel T helper subset (Th10 cells), respectively. Th10 cells are expanded in the blood of SLE patients and accumulate within the tubuloinsterstitial areas of proliferative nephritis (PLN) lesions. These cells produce IL10 and mitochondrial ROS (mtROS) as the result of reverse electron transport (RET) fueled by the tricarboxylic acid (TCA) cycle intermediate succinate. Functionally, Th10 cells are not suppressive, but they provide B cell help through the synergistic effect of IL10 and succinate. The mechanisms responsible for the acquisition of a regulatory versus a helper phenotype remain elusive. We now show that naïve CD4+ T cells require the activation of the Delta Like Canonical Notch Ligand 4 (Dll4)-Notch pathway in order to acquire a TH10 phenotype. Conversely, the TLR7-IRF7 pathway is necessary for the generation of Tr1 cells. These pathways might be exploited for therapeutic intervention in human autoimmune diseases.
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Martín-Nares, Eduardo, Gabriela Hernández-Molina, Ángel A. Priego-Ranero, Isela Chan-Campos, Gladys S. Herrera-Noguera, Fidel López-Verdugo, and Janette Furuzawa-Carballeda. "Peripheral Immunophenotype in IgG4-Related Disease and Its Association with Clinical Phenotypes and Disease Activity." Cells 12, no. 4 (February 20, 2023): 670. http://dx.doi.org/10.3390/cells12040670.
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Diverse immune cell subsets have been described in IgG4-related disease (IgG4-RD). If there is a different immunophenotype according to clinical phenotype and activity status is not known. Levels of IL-4-, IL-13-, IL-5-, and IL-21-producing CD4+ T cells (Th2 subsets), CD4+ cytotoxic T lymphocytes (CD4+CTLs), T helper 9 cells, T follicular helper cells (Tfh; Tfh1/Tfh2/Tfh17/Tf regulatory [Tfr]), Foxp3+ regulatory T cells, Type 1 regulatory T cells (Tr1), T helper 3 regulatory cells (Th3), IL-10-producing regulatory B cells (Bregs), IL-10-expressing regulatory plasmacytoid dendritic (pDC IL-10+) cells, and M1 and M2 monocytes were determined by flow cytometry in 43 IgG4-RD patients and 12 controls. All immune subsets were higher in patients vs. controls. CD4+/IL-4+, CD4+/IL-5+, CD4+CTLs, Tfh2, Tfh17, Tfr, and M1 monocyte cell number was different among IgG4-RD clinical phenotypes. The pancreato-hepato-biliary phenotype was characterized by a higher CD4+CTLs, Tfh17, Tfh2, and Tfr and lower M1 cell number. An increased CD4+CTLs and Th3 cell number distinguished the head and neck-limited phenotype, while the retroperitoneal/aortic and Mikulicz/systemic phenotypes were characterized by increased Th2 subsets. Tfh17, Tr1, Th3, pDC, M1, and M2 monocytes were augmented in active patients. In summary, the clinical heterogeneity of IgG4-RD might be driven by the participation of different immunophenotypes and, consequently, by a different fibroinflammatory process.
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Jasiecka-Mikołajczyk, Agnieszka, Jerzy J. Jaroszewski, and Tomasz Maślanka. "Oclacitinib, a Janus Kinase Inhibitor, Reduces the Frequency of IL-4- and IL-10-, but Not IFN-γ-, Producing Murine CD4+ and CD8+ T Cells and Counteracts the Induction of Type 1 Regulatory T Cells." Molecules 26, no. 18 (September 17, 2021): 5655. http://dx.doi.org/10.3390/molecules26185655.
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The purpose of the present study was to broaden the knowledge and understanding of the effects of oclacitinib (OCL), a Janus kinase inhibitor, on T cells in the context of both the immune mechanisms underlying anti-inflammatory and anti-allergic properties of the drug and its safety. The results indicate that beneficial effects of OCL in the treatment of skin allergic diseases may be partially mediated by the inhibition of IL-4 production in CD4+ and CD8+ T cells. To a certain extent, the antiproliferative effect of OCL on CD8+ T cells may also contribute to its therapeutic effect. The study found that OCL does not affect the proliferation of CD4+ T cells or the number of IFN-γ- and IL-17-producing CD4+ and CD8+ T cells. Moreover, OCL was found to counteract the induction of type 1 regulatory T (Tr1) cells and to act as a strong inhibitor of IL-10 production in both CD4+ and CD8+ T cells. Thus, these results indicate that beneficial effects of OCL in the treatment of skin allergic diseases are not mediated through: (a) the abolishment of IFN-γ and IL-17-production in CD4+ and CD8+ T cells; (b) generation of Tr1 cells; (c) inhibition of CD4+ T cell proliferation; (d) induction of IL-10 production in CD4+ T cells. The results of this study strongly suggest that, with respect to the evaluated parameters, OCL exerts a suppressive effect on Th2- but not Th1-mediated immunity.
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Belizário, José E., Wesley Brandão, Cristiano Rossato, and Jean Pierre Peron. "Thymic and Postthymic Regulation of Naïve CD4+T-Cell Lineage Fates in Humans and Mice Models." Mediators of Inflammation 2016 (2016): 1–16. http://dx.doi.org/10.1155/2016/9523628.
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Our understanding of how thymocytes differentiate into many subtypes has been increased progressively in its complexity. At early life, the thymus provides a suitable microenvironment with specific combination of stromal cells, growth factors, cytokines, and chemokines to induce the bone marrow lymphoid progenitor T-cell precursors into single-positive CD4+and CD8+T effectors and CD4+CD25+T-regulatory cells (Tregs). At postthymic compartments, the CD4+T-cells acquire distinct phenotypes which include the classical T-helper 1 (Th1), T-helper 2 (Th2), T-helper 9 (Th9), T-helper 17 (Th17), follicular helper T-cell (Tfh), and induced T-regulatory cells (iTregs), such as the regulatory type 1 cells (Tr1) and transforming growth factor-β- (TGF-β-) producing CD4+T-cells (Th3). Tregs represent only a small fraction, 5–10% in mice and 1-2% in humans, of the overall CD4+T-cells in lymphoid tissues but are essential for immunoregulatory circuits mediating the inhibition and expansion of all lineages of T-cells. In this paper, we first provide an overview of the major cell-intrinsic developmental programs that regulate T-cell lineage fates in thymus and periphery. Next, we introduce the SV40 immortomouse as a relevant mice model for implementation of new approaches to investigate thymus organogenesis, CD4 and CD8 development, and thymus cells tumorogenesis.
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Wu, Sihan, Rui Ma, Yajie Zhong, Zilin Chen, Hongyan Zhou, Minyi Zhou, Waipo Chong, and Jun Chen. "Deficiency of IL-27 Signaling Exacerbates Experimental Autoimmune Uveitis with Elevated Uveitogenic Th1 and Th17 Responses." International Journal of Molecular Sciences 22, no. 14 (July 14, 2021): 7517. http://dx.doi.org/10.3390/ijms22147517.
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Human uveitis is an autoimmune disease of the central nervous system that is characterized by ocular inflammation with the involvement of uveitogenic Th1 and Th17 responses. In experimental autoimmune uveitis (EAU), the animal model for human uveitis, both responses are proven to be critical in disease development. Therefore, targeting both Th1 and Th17 cells has therapeutic implication for disease resolution. IL-27 is a multifunctional cytokine that can either promote or inhibit T cell responses and is implicated in both autoimmune and infectious diseases. The aim of this study is to characterize the role of IL-27/IL-27R signaling in regulating uveitogenic Th1/Th17 responses in EAU. By immunizing IL-27Rα−/− mice and their wild-type (WT) littermates for EAU, we demonstrated that IL-27 signaling deficiency exacerbated EAU with severe ocular inflammation and impairment of visual function. Furthermore, there was a significant increase in the eye-infiltrating Th1 and Th17 cells in IL-27Rα−/− EAU mice compared to WT. Their retinal antigen-specific Th1 and Th17 responses were also significantly increased, as represented by the elevation of their signature cytokines, IFN-γ and IL-17A, respectively. We also observed the upregulation of another pathogenic cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF), from effector T cells in IL-27Rα−/− EAU mice. Mechanistic studies confirmed that IL-27 inhibited GM-CSF production from Th17 cells. In addition, the induction of IL-10 producing type 1 regulatory T (Tr1) cells was impaired in IL-27Rα−/− EAU mice. These results identified that IL-27 signaling plays a suppressive role in EAU by regulating multiple CD4+ cell subsets, including the effector Th1 and Th17 cells and the regulatory Tr1 cells. Our findings provide new insights for therapeutic potential in controlling uveitis by enhancing IL-27 signaling.
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Gol-Ara, Maryam, Farhad Jadidi-Niaragh, Reza Sadria, Gholamreza Azizi, and Abbas Mirshafiey. "The Role of Different Subsets of Regulatory T Cells in Immunopathogenesis of Rheumatoid Arthritis." Arthritis 2012 (October 24, 2012): 1–16. http://dx.doi.org/10.1155/2012/805875.
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Rheumatoid arthritis (RA) is a common autoimmune disease and a systemic inflammatory disease which is characterized by chronic joint inflammation and variable degrees of bone and cartilage erosion and hyperplasia of synovial tissues. Considering the role of autoreactive T cells (particularly Th1 and Th17 cells) in pathophysiology of RA, it might be assumed that the regulatory T cells (Tregs) will be able to control the initiation and progression of disease. The frequency, function, and properties of various subsets of Tregs including natural Tregs (nTregs), IL-10-producing type 1 Tregs (Tr1 cells), TGF-β-producing Th3 cells, CD8+ Tregs, and NKT regulatory cells have been investigated in various studies associated with RA and collagen-induced arthritis (CIA) as experimental model of this disease. In this paper, we intend to submit the comprehensive information about the immunobiology of various subsets of Tregs and their roles and function in immunopathophysiology of RA and its animal model, CIA.
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Xiao, Sheng, and Vijay Kuchroo. "Tim-1 is essential for induction and maintenance of IL-10 in regulatory B cells and their regulation of tissue inflammation (IRC11P.435)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 197.17. http://dx.doi.org/10.4049/jimmunol.194.supp.197.17.
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Abstract T cell Ig and mucin domain (Tim)-1 identifies IL-10-producing regulatory B cells (Bregs). Mice on the C57BL/6 background harboring a loss of function Tim-1 mutant showed progressive loss of IL-10 production in B cells and with age developed severe multi-organ tissue inflammation. We demonstrate that Tim-1 expression and signaling in Bregs are required for optimal production of IL-10. B cells with Tim-1 defects have impaired IL-10 production but increased proinflammatory cytokine production including IL-1 and IL-6. Tim-1-deficient B cells promote Th1 and Th17 responses but inhibit the generation of regulatory T cells (Foxp3+ and IL-10-producing type 1 regulatory T (Tr1) cells) and enhance the severity of experimental autoimmune encephalomyelitis (EAE). Mechanistically, Tim-1 on Bregs is required for apoptotic cell (AC) binding to Bregs and for AC-induced IL-10 production in Bregs. Treatment with AC reduces EAE severity in wildtype (WT) but not Tim-1-deficient Bregs. Collectively, these findings suggest that in addition to serving as a marker for identifying IL-10-producing Bregs, Tim-1 is also critical for maintaining self-tolerance by regulating IL-10 production in Bregs.
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Andolfi, Grazia, Georgia Fousteri, Maura Rossetti, Chiara F. Magnani, Tatiana Jofra, Grazia Locafaro, Attilio Bondanza, Silvia Gregori, and Maria-Grazia Roncarolo. "Enforced IL-10 Expression Confers Type 1 Regulatory T Cell (Tr1) Phenotype and Function to Human CD4+ T Cells." Molecular Therapy 20, no. 9 (September 2012): 1778–90. http://dx.doi.org/10.1038/mt.2012.71.
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Le Buanec, H., M. L. Gougeon, A. Mathian, P. Lebon, J. M. Dupont, G. Peltre, P. Hemon, et al. "IFN- and CD46 stimulation are associated with active lupus and skew natural T regulatory cell differentiation to type 1 regulatory T (Tr1) cells." Proceedings of the National Academy of Sciences 108, no. 47 (November 7, 2011): 18995–9000. http://dx.doi.org/10.1073/pnas.1113301108.
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Hong, Chien-Hui, Shang-Hung Lin, Björn E. Clausen, and Chih-Hung Lee. "Selective AhR knockout in langerin-expressing cells abates Langerhans cells and polarizes Th2/Tr1 in epicutaneous protein sensitization." Proceedings of the National Academy of Sciences 117, no. 23 (May 27, 2020): 12980–90. http://dx.doi.org/10.1073/pnas.1917479117.
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The aryl hydrocarbon receptor (AhR) represents an environmental sensor regulating immune responses. In the skin, AhR is expressed in several cell types, including keratinocytes, epidermal Langerhans cells (LC), and dermal dendritic cells (DC). The mechanisms how AhR activates or inhibits cutaneous immune responses remain controversial, owing to differences in the cell-specific functions of AhR and the different activating ligands. Therefore, we sought to investigate the role of AhR in LC and langerin+and negative DC in the skin. To this aim, we generated Langerin-specific and CD11c-specific knockout (−/−) mice lacking AhR, respectively, in LC and Langerin+dermal DC and in all CD11c+cells. These were then tested in an epicutaneous protein (ovalbumin, Ova) sensitization model. Immunofluorescence microscopy and flow cytometry revealed that Langerin-AhR−/−but not CD11c-AhR−/−mice harbored a decreased number of LC with fewer and stunted dendrites in the epidermis as well as a decreased number of LC in skin-draining lymph nodes (LN). Moreover, in the absence of AhR, we detected an enhanced T helper type-2 (Th2) [increased interleukin 5 (IL-5) and interleukin 13 (IL-13)] and T regulatory type-1 (Tr1) (IL-10) response when LN cells were challenged with Ova in vitro, though the number of regulatory T cells (Treg) in the LN remained comparable. Langerin-AhR−/−mice also exhibited increased blood levels of Ova-specific immunoglobulin E (IgE). In conclusion, deletion of AhR in langerin-expressing cells diminishes the number and activation of LC, while enhancing Th2 and Tr1 responses upon epicutaneous protein sensitization.
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Chujo, Daisuke, Akitsu Kawabe, Maya Matsushita, Nobuyuki Takahashi, Chiharu Tsutsumi, Fumitaka Haseda, Akihisa Imagawa, et al. "Distinct Phenotypes of Islet Antigen-Specific CD4+ T Cells Among the 3 Subtypes of Type 1 Diabetes." Journal of Clinical Endocrinology & Metabolism 105, no. 10 (July 11, 2020): 3141–51. http://dx.doi.org/10.1210/clinem/dgaa447.
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Abstract Context Type 1 diabetes (T1D) is classified into 3 subtypes: acute-onset (AT1D), slowly progressive (SP1D), and fulminant (FT1D). The differences in the type of cellular autoimmunity within each subtype remain largely undetermined. Objective To determine the type and frequency of islet antigen-specific CD4+ T cells in each subtype of T1D. Participants Twenty patients with AT1D, 17 with SP1D, 18 with FT1D, and 17 persons without diabetes (ND). Methods We performed an integrated assay to determine cellular immune responses and T-cell repertoires specific for islet antigens. This assay included an ex vivo assay involving a 48-hour stimulation of peripheral blood mononuclear cells with antigen peptides and an expansion assay involving intracytoplasmic cytokine analysis. Results The results of the ex vivo assay indicated that glutamic acid decarboxylase 65 (GAD65)-specific interleukin-6 and interferon-inducible protein-10 (IP-10) responses and preproinsulin (PPI)-specific IP-10 responses were significantly upregulated in AT1D compared with those of ND. Furthermore, GAD65- and PPI-specific granulocyte colony-stimulating factor responses were significantly upregulated in FT1D. Expansion assay revealed that GAD65- and PPI-specific CD4+ T cells were skewed toward a type 1 helper T (Th1)- cell phenotype in AT1D, whereas GAD65-specific Th2 cells were prevalent in SP1D. GAD65-specific Th1 cells were more abundant in SP1D with human leukocyte antigen-DR9 than in SP1D without DR9. FT1D displayed significantly less type 1 regulatory T (Tr1) cells specific for all 4 antigens than ND. Conclusions The phenotypes of islet antigen-specific CD4+ T cells differed among the three T1D subtypes. These distinct T-cell phenotypes may be associated with the manner of progressive β-cell destruction.
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Jasiecka-Mikolajczyk, Agnieszka, Piotr Socha, Jerzy Jan Jaroszewski, and Tomasz Maslanka. "Oclacitinib induces Foxp3 expression in CD4+ T cells under activation conditions." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 92.26. http://dx.doi.org/10.4049/jimmunol.204.supp.92.26.
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Abstract Oclacitinib (OCL) is a novel immunosuppressive agent approved for dogs that controls inflammation in allergic disease via the inhibition of the JAK/STAT pathway. The present study attempts to shed light on the involvement of Foxp3-expressing regulatory CD4+ T (Treg) cells and inducible type 1 regulatory T (Tr1) cells in the anti-inflammatory and anti-allergic actions of OCL. Our previous study demonstrated that exposure of unstimulated canine lymphocytes to OCL did not affect Foxp3 expression in T cells. This study investigates the effect of OCL on Foxp3 expression by canine CD4+ T cells in the course of in vitro activation. Effect of OCL on generation of Tr1 (i.e. CD223+CD49b+CD4+) cells was studied using murine lymphocytes due to the lack of appropriate antibodies for the induction and detection of these cells in dogs. The exposure of canine lymphocytes to both concentration of OCL, with a concomitant stimulation, led to a significant increase in the percentage of Foxp3-expressing cells within the CD4+ T cell subset. In the light of our previous results, it can be suggested that the effect of OCL on Foxp3 expression in CD4+ T cells may depend on T cell activation status. The mean percentage of CD3/CD28-induced CD223+CD49b+CD4+ T cells was approximately 6- and 2-fold lower in the cultures exposed to OCL 10−6 and 10−7M, respectively, compared to untreated cells. Thus, the results strongly suggest that the generation of inducible Foxp3-expressing CD4+ T cells may constitute one of mechanisms responsible for the production of anti-inflammatory and anti-allergic effects of OCL. These effects are not mediated by generation of Tr1 cells. What is more, the present results indicate that OCL may counteract the induction of these cells.
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Xia, Chang-Qing, Anna Chernatynskaya, Clive Wasserfall, Benjamin Looney, Suigui Wan, Michael Clare-Salzler, and Mark Atkinson. "Anti-Thymocyte Globulin (ATG) Differentially Depletes naïve and Memory T Cells and Permits Memory-Type Regulatory T Cells." Blood 120, no. 21 (November 16, 2012): 4670. http://dx.doi.org/10.1182/blood.v120.21.4670.4670.
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Abstract Abstract 4670 Anti-thymocyte globulin (ATG) has been used in clinic for the treatment of allograft rejection and autoimmune diseases. However, its mechanism of action is not fully understood. To our knowledge, how ATG therapy affects naïve and memory T cells has not been well investigated. In this study, we have employed nonobese diabetic mouse model to investigate how administration of anti-thymocyte globulin (ATG) affects memory and naïve T cells as well as CD4+CD25+Foxp3+ regulatory T cells in peripheral blood and lymphoid organs; We also investigate how ATG therapy affects antigen-experienced T cells. Kinetic studies of peripheral blood CD4+ and CD8+ T cells post-ATG therapy shows that both populations decline to their lowest levels at day 3, while CD4+ T cells return to normal levels more rapidly than CD8+ T cells. We find that ATG therapy fails to eliminate antigen-primed T cells, which is consistent with the results that ATG therapy preferentially depletes naïve T cells relative to memory T cells. CD4+ T cell responses post-ATG therapy skew to T helper type 2 (Th2) and IL-10-producing T regulatory type 1 (Tr1) cells. Intriguingly, Foxp3+ regulatory T cells (Tregs) are less sensitive to ATG depletion and remain at higher levels following in vivo recovery compared to controls. Of note, the frequency of Foxp3+ Tregs with memory-like immunophenotype is significantly increased in ATG-treated animals, which might play an important role in controlling effector T cells post ATG therapy. In summary, ATG therapy may modulate antigen-specific immune responses through modulation of naïve and memory T cell pools and more importantly through driving T cell subsets with regulatory activities. This study provides important data for guiding ATG therapy in allogenieic hematopoietic stem cell transplantation and other immune-mediated disorders. Disclosures: No relevant conflicts of interest to declare.
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Rowe, H., A. Watad, T. Russell, K. Sharif, D. Newton, M. Wittmann, Q. Zhou, et al. "SAT0361 HEALTHY HUMAN SPINAL PROCESSES PERI-ENTHESEAL T-CELLS EXHIBIT A TR1 RATHER THAN A FOXP3 REGULATORY PHENOTYPE." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1127.2–1128. http://dx.doi.org/10.1136/annrheumdis-2020-eular.6689.
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Background:We have previously reported that the normal spinal enthesis has populations of conventional T-cells including CD4+ & CD8+ T-cells that could be induced to produce IL-17A and TNF following anti-CD3/CD28 stimulation. The biology of such cells in health including their normal function and antigen reactivity is completely unknown. The purpose of this work was to define the phenotype, functionality and TCR reactivity of such T-cells in health.Objectives:To investigate whether the T-cells at the normal enthesis were regulatory in nature and to determine the type of regulatory T-cell as Tr1 or FOXP3 regulatory T-cell and to determine T-cell reactivity.Methods:Healthy interspinous ligament and spinous process with matched peripheral blood were harvested from patients undergoing elective spinal surgery (n=20). Entheseal soft tissue (EST) & peri-entheseal bone (PEB) was enzymatically digested and then sorted. Tr1 and Treg phenotypes were investigated using flow cytometry. Analysis of cytokines, growth factors and chemokines was performed by qRT-PCR, ELISA and flow cytometry. TCR sequencing was performed and a search for putative T-cell reactivity was done using TCR3 database.Results:Pro-inflammatory cytokine transcripts including IL-17A, IL-17F, IL-22, IL-23 (p19) & TNF were very low or undetectable in the Enthesis T-cells (Fig 1). Flow cytometry confirmed entheseal T-cells had a Tr1 phenotype (CD4+ LAG3+ CD49b+). Intracellular flow cytometry showed enthesis T-cells had very low FOXP3 expression, when compared to their blood counterparts. Intracellular flow cytometry and gene expression showed high basal expression of growth factors and regulatory proteins such as IL-10 & TGFβ, when compared to blood T-cells. RNA-Seq data, showed 13 potential TCR clonal sequences the most common of which are predicted to be reactive viral infection was CMV present in 8 sequences and Influenza A virus present in 2 sequences.Conclusion:The healthy human enthesis has regulatory T-cells of a Tr1 phenotype rather than a FOXP3 Treg phenotype. Many clones have antigen specificity indicating reactivity to prior infection. These findings suggest that conventional entheseal T-cells have a role in enthesis immune homeostasis.Disclosure of Interests:Hannah Rowe Grant/research support from: Novartis UK Investigator Initiated non-clinical research funding support, Abdulla Watad: None declared, Tobias Russell Grant/research support from: Novartis UK Investigator Initiated non-clinical research funding support, Kassem Sharif: None declared, Darren Newton: None declared, Miriam Wittmann: None declared, Qiao Zhou Grant/research support from: Funded by the PARTNER fellowship program, Almas Khan: None declared, Peter Loughenbury: None declared, Robert Dunsmuir: None declared, Abhay S Rao: None declared, Peter Millner: None declared, Tony Kenna: None declared, Matthew Brown: None declared, Charlie Bridgewood: None declared, Dennis McGonagle Grant/research support from: Janssen Research & Development, LLC