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1
Ohta, Nobuo, Shigeru Fukase, Takeo Fuse, and Masaru Aoyagi. "Th1 and Th2 CD4+ T cells and Tc1 and Tc2 CD8+ T cells of patients with Wegener’s granulomatosis." Journal of Laryngology & Otology 116, no. 8 (August 2002): 605–9. http://dx.doi.org/10.1258/00222150260171597.
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A Th1/Th2 cytokine imbalance with a predominance of Th1 cytokines has been suggested to be of pathogenic importance in Wegener’s granulomatosis. To evaluate the role of Th1/Th2 cytokines in Wegener’s granulomatosis, the subsets of Th1, Th2, Tc1 and Tc2 cells from patients with active Wegener’s granulomatosis were examined by intracellular cytokine flow cytometry. The population of Tc1 cells (72.0 ± 14.4 per cent) in Wegener’s granulomatosis was significantly increased compared with Tc1 cells (37.3 ± 14.6 per cent) in control (p<0.05). Th1, Th2 and Tc2 cells in Wegener’s granulomatosis were not significantly increased compared with the control cells. These results indicate that the predominance of Tc1 cells might contribute to the mechanism of the pathogenesis of Wegener’s granulomatosis.
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Gajewski, T. F., D. W. Lancki, R. Stack, and F. W. Fitch. ""Anergy" of TH0 helper T lymphocytes induces downregulation of TH1 characteristics and a transition to a TH2-like phenotype." Journal of Experimental Medicine 179, no. 2 (February 1, 1994): 481–91. http://dx.doi.org/10.1084/jem.179.2.481.
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Mature CD4+ helper T lymphocytes have been categorized into two major functional phenotypes, TH1 and TH2, which produce distinct arrays of lymphokines and which are thought to arise from a pluripotential precursor cell termed TH0. Clonal anergy can be induced in TH1 clones by stimulating via the T cell receptor (TCR) complex in the absence of a costimulator molecule; however, anergy has been difficult to demonstrate in TH2 clones. We show here that treatment of cloned TH0 lines with anergizing stimuli results in the selective loss of TH1 characteristics and retention of a TH2 phenotype. Treated cells exhibit a substantial reduction in interleukin 2 (IL-2) production and antigen-specific cytolytic activity, but retain comparable IL-4 and IL-5 production in response to restimulation via the TCR complex. TH0 clones exposed to anergizing stimuli also increase in size, thus morphologically resembling TH2 cells. The signaling characteristics of these cells also are altered, in that they exhibit an elevated basal level of intracellular free calcium which fails to increase significantly with subsequent restimulation, reminiscent of the signaling characteristics of TH2 cells. "Anergized" TH0 clones thus share several functional, morphologic, and physiologic properties with cells of the TH2 phenotype, suggesting that TH2 cells may arise when TH0 cells are stimulated via the TCR complex in the absence of a putative costimulator molecule.
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Singh, Rana A. K., Ying C. Q. Zang, Anju Shrivastava, Jian Hong, George T. Wang, Sufang Li, Maria V. Tejada-Simon, Milena Kozovska, Victor M. Rivera, and Jingwu Z. Zhang. "Th1 and Th2 Deviation of Myelin-Autoreactive T Cells by Altered Peptide Ligands Is Associated with Reciprocal Regulation of Lck, Fyn, and ZAP-70." Journal of Immunology 163, no. 12 (December 15, 1999): 6393–402. http://dx.doi.org/10.4049/jimmunol.163.12.6393.
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Abstract Th0 clones recognizing an immunodominant peptide of myelin basic protein (residues 83–99) were derived from patients with multiple sclerosis. We demonstrate that analogue peptides with alanine substitution at Val86 and His88 had a unique partial agonistic property in inducing Th0 →Th1 and Th0 →Th2 deviation of the myelin basic protein-reactive T cell clones, respectively. Th0 to Th1 deviation induced by peptide 86V→A correlated with up-regulation of Fyn and ZAP-70 kinase activities. Conversely, Th0 to Th2 deviation induced by peptide 88H→A was associated with complete failure to activate Fyn and ZAP-70 kinases. The observed Th1 and Th2 shift also correlated, to a lesser extent, with Lck kinase activity that was down-regulated with Th1 deviation and increased with Th2 deviation in some T cell clones. We demonstrated that the Th1 and Th2 shift induced by the analogue peptides was a reversible process, as the T cell clones previously exposed to either 86V→A or 88H→A peptide could revert to an opposite phenotype when rechallenged reciprocally with a different analogue peptide. The study has important implications in our understanding of regulation of TCR-associated tyrosine kinases by altered peptide ligands and its role in cytokine regulation of autoreactive T cells.
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Miner, Kent T., and Michael Croft. "Generation, Persistence, and Modulation of Th0 Effector Cells: Role of Autocrine IL-4 and IFN-γ." Journal of Immunology 160, no. 11 (June 1, 1998): 5280–87. http://dx.doi.org/10.4049/jimmunol.160.11.5280.
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Abstract Many studies have classified CD4 responses into either Th1-like or Th2-like, based on cytokine secretion profiles, but little significance has been placed on Th0 cells. This has largely resulted from studies that suggested that Th0 populations primarily comprise individual Th1 and Th2 cells. Here, we show that priming of Ag-specific naive CD4 cells with moderate dose IL-4 generates a Th0 population that is evident after 3 days in vitro and becomes prevalent after successive encounters with Ag over a 9-day period. By intracellular cytokine staining, the majority (>60%) of effector cells generated in this way produce either IL-4, IFN-γ and IL-2, or IL-4 and IFN-γ without IL-2. Endogenous IFN-γ secreted over the initial 3 days of culture was critical for generating Th0 cells, since neutralization allowed IL-4 to induce differentiation into Th2-like cells. Successive encounters with Ag were required for generating Th0 cells, and their stability and persistence were governed by the balance of endogenous IL-4 and IFN-γ secreted during the later stages of differentiation. Studies blocking Fas-induced cell death showed that this process played no role in Th0 cell generation, and differential death of committed Th1 or Th2 cells was not required for Th0 persistence. These data suggest that Th0 cells can be as prevalent as Th1- or Th2-like cells after naive CD4 activation, that the relative levels of autocrine IL-4 and IFN-γ are important to the lack of commitment, and that not all cells are predestined to the Th1 or Th2 phenotypes early in the response.
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Groux, H., T. Sornasse, F. Cottrez, J. E. de Vries, R. L. Coffman, M. G. Roncarolo, and H. Yssel. "Induction of human T helper cell type 1 differentiation results in loss of IFN-gamma receptor beta-chain expression." Journal of Immunology 158, no. 12 (June 15, 1997): 5627–31. http://dx.doi.org/10.4049/jimmunol.158.12.5627.
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Abstract Differential expression of cytokine receptors accounts for an important regulatory mechanism in differentiation of Th1/Th2 subsets. Here, we report that human Th0 and Th2 clones constitutively express transcripts for the IFN-gammaR beta-chain, whereas mRNA for this signaling component of the IFN-gamma receptor is absent in Th1 clones. Activation of T cell clones, however, resulted in a transient induction or enhancement of IFN-gammaR beta-chain mRNA expression in Th1 clones and Th0/Th2 clones, respectively. IL-12-mediated Th1 cell differentiation of naive CD4+, CD45RA+ cord blood T cells, which constitutively express IFN-gammaR beta-chain mRNA, resulted in a loss of expression of this cytokine receptor chain after 6 to 12 days of culture. In contrast, Th2 populations, differentiated from CD4+, CD45RA+ cord blood T cells in the presence of IL-4, continued to express high levels of IFN-gammaR beta-chain transcripts. The loss of IFN-gammaR beta-chain expression in Th1 populations was accompanied by a failure of IFN-gamma to induce the expression of the IFN-gamma-inducible gene, IFN response factor-1, whereas IFN-gamma was effective in inducing IFN response factor-1 mRNA expression in Th0 and Th2 cells. These results indicate that down-regulation of the IFN-gammaR beta-chain correlates with impaired IFN-gamma-induced signaling in Th1 cells. Finally, Th2 populations, generated in the presence of both IL-4 and IFN-gamma, expressed levels of IFN-gammaR beta-chain transcripts similar to those produced by cells differentiated in the presence of IL-4 only, demonstrating that IFN-gamma does not modulate the expression of its receptor. Together, these data indicate that human Th0/Th2 and Th1 subsets, respectively, can be distinguished based on the expression of the IFN-gammaR beta-chain.
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Mumpuni, A., H. S. S. Sharma, and Averil E. Brown. "Effect of Metabolites Produced by Trichoderma harzianum Biotypes and Agaricus bisporus on Their Respective Growth Radii in Culture." Applied and Environmental Microbiology 64, no. 12 (December 1, 1998): 5053–56. http://dx.doi.org/10.1128/aem.64.12.5053-5056.1998.
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ABSTRACT Trichoderma harzianum biotypes Th1, Th2, and Th3 produced volatile metabolites in vitro which had similar fungistatic effects on the growth of Agaricus bisporus. Metabolites present in agar colonized by these strains also inhibited mycelial growth of A. bisporus, although the reduction in growth was less in the presence of metabolites produced by biotype Th2 than that in the presence of metabolites produced by Th1 or Th3.A. bisporus produced metabolites in liquid culture that inhibited the growth of Th1 and Th3 but stimulated the growth of Th2. A compound(s) responsible for the inhibition and stimulation was extracted from A. bisporus culture filtrate and from compost-grown fruit bodies with n-butanol, but the identity of the compound(s) was not determined. We suggest that the stimulation of Th2 by metabolites produced by A. bisporus and the relatively low level of inhibition of A. bisporus by Th2 facilitate colonization of compost by both fungi. However, as compost colonization reaches a maximum, a change in the competitive balance in favor of Th2 results in the inhibition of fruit body production by A. bisporus and the devastating green mold epidemics affecting mushroom production.
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Mouzaki, Athanasia, Maria Theodoropoulou, Ioannis Gianakopoulos, Vassiliki Vlaha, Maria-Christina Kyrtsonis, and Alice Maniatis. "Expression patterns of Th1 and Th2 cytokine genes in childhood idiopathic thrombocytopenic purpura (ITP) at presentation and their modulation by intravenous immunoglobulin G (IVIg) treatment: their role in prognosis." Blood 100, no. 5 (September 1, 2002): 1774–79. http://dx.doi.org/10.1182/blood.v100.5.1774.h81702001774_1774_1779.
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Childhood idiopathic thrombocytopenic purpura (ITP) resolves usually after the first episode, although it may recur, and in 10% to 20% of patients develops into a chronic disorder. Evidence of the immunoregulatory role of Th1/Th2 responses in autoimmune diseases prompted us to perform a prospective study of Th1/Th2 gene expression profiles and transforming growth factor β (TGF-β) plasma levels in 18 children (median age, 6.4 years) with acute ITP, before and after intravenous immunoglobulin G (IVIg) infusion, and during a follow-up period (0.5-5 years). Initially, 12 of 18 patients had either low Th0/Th1 plus interleukin 10 (IL-10) or no in vivo cytokine gene expression (0). At 24 hours after IVIg infusion this pattern became 0 or Th2 (9 of 12) or remained low Th0/Th1 (3 of 12). During follow-up these patients did not relapse and maintained 0 or Th2 pattern without IL-10. Of the remaining 6 patients, 4 presented with a Th1 or Th0/Th1 pattern plus IL-10 that persisted after IVIg treatment (although interferon γ [IFN-γ] expression diminished) and stabilized to Th1 plus IL-10 at follow-up, which was marked by infrequent episodes of ITP. Two patients presenting with a strict Th1 pattern characterized by high expression of IFN-γ, which remained unchanged after IVIg and at follow-up, can be characterized as chronic ITP. TGF-β plasma levels were low in patients with active disease and increased in remission. Overall, acute ITP presents with Th1, Th0/Th1, or 0 in vivo cytokine gene expression. Stable remission is associated with a 0 or Th2 pattern. A 0 or Th2 pattern after IVIg gave the best prognosis, whereas sustained high expression of IFN-γ and refractoriness to IVIg were the main indicators of poor prognosis.
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Hsieh, Chia-Chen, Wen-Huang Peng, Hsien-Hao Tseng, Shan-Yuan Liang, Li-Jen Chen, and Jen-Chieh Tsai. "The Protective Role of Garlic on Allergen-Induced Airway Inflammation in Mice." American Journal of Chinese Medicine 47, no. 05 (January 2019): 1099–112. http://dx.doi.org/10.1142/s0192415x19500563.
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Asthma is the most prevalent chronic respiratory disease worldwide. Garlic extracts have long been used as a food source and in traditional medicine. Crude extracts of garlic are used as an anti-inflammatory agent and have been reported to exhibit antiasthmatic properties. However, molecular mechanisms of garlic extracts in the context of antiasthmatic airway inflammation are still unclear. In this study, the antiasthmatic effect of garlic extracts on Th1, Th2, and Th3 cytokine profiles and immunoregulatory mechanism were explored using an animal model of allergic asthma. Garlic extracts significantly reduced total inflammatory cell counts and eosinophil infiltration and decreased the production of Dermatophagoides pteronyssinus IgE in serum and Th1/Th2/Th3 cytokine in bronchoalveolar fluid. Enzyme-linked immunosorbent assay analysis demonstrated that garlic extracts downregulated the levels of cytokines and chemokines, namely Th2-related IL-4, IL-5, and IL-13; but they simultaneously upregulated Th1-related IFN-[Formula: see text], IL-12, and Th3-related IL-10 and TGF-[Formula: see text] expression in BALF. The mechanism may be ascribed to the modulation of Th1-, Th2-, and Th3-related cytokine imbalance.
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Jagannath, Chinnaswamy, Cherie Michelle Roche, and Ashish Arora. "Dendritic cells pulsed with either secretory antigens of Mycobacterium tuberculosis or live mycobacteria show a differential expansion of Th1, Th2 and Th3 type T cells in immune mice (92.10)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S164. http://dx.doi.org/10.4049/jimmunol.178.supp.92.10.
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Abstract Dendritic cells (DCs) can prime naïve or immune T cells and expand Th1, Th2 and Th3 type of T cells that determine protection against pathogens. While the Th1 immunity has been thought to be protective against tuberculosis, the ability of vaccines to induce Th1-Th3 immunity is unclear. Emerging tuberculosis vaccines include DNA vaccines encoding 85 complex (A, B, C), ESAT-6 and CFP-10 (ES antigens) or live attenuated Mycobacterium tuberculosis (MTB) in comparison with BCG vaccine. Interestingly, MTB H37Rv secretes all three ES antigens while BCG secretes Ag85 but lacks ESAT-6 and CFP-10. We therefore hypothesized that ES antigens and live bacteria may induce different types of T cell responses and the efficacy of vaccines delivering these would vary in mice. METHODS: Bone marrow derived C57Bl/6 DCs were infected with live H37Rv or BCG or were pulsed with Ag85(ABC), ESAT-6 or CFP-10 antigens. After 24 h, they were cocultured with naïve T cells or immune T cells from heat killed MTB immunized mice. T cells were then stained for intracellular T-bet/IFN-γ, GATA3/IL-4 and Foxp3/IL-10 to determine the expansion of Th1, Th2 and Th3 response respectively. RESULTS: ES antigens induced a strong Th1 response with very little Th2 or Th3 responses in immune T cells. Paradoxically, H37Rv and BCG induced a Th1 response as well as significant levels of Th2 and Th3 type of T cells. CONCLUSIONS: We suggest that live mycobacterial vaccines concurrently induce deleterious Th2 and Th3 T cells during vaccination or infection that may affect the protective function of Th1 T cells.
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Jeannin, P., Y. Delneste, M. Seveso, P. Life, and J. Y. Bonnefoy. "IL-12 synergizes with IL-2 and other stimuli in inducing IL-10 production by human T cells." Journal of Immunology 156, no. 9 (May 1, 1996): 3159–65. http://dx.doi.org/10.4049/jimmunol.156.9.3159.
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Abstract IL-12, a potent inducer of IFN-gamma production by T cells and NK cells, has been recently reported to exacerbate an established Th2 response in vivo. However, the effect of IL-12 on Th2-lymphokine production remains unclear. Since IL-10 is a lymphokine associated with Th2 responses which decreases both IL-12-induced IFN-gamma production and IL-12 production by macrophages, we have analyzed here, in an APC-free system, the ability of IL-12 to modulate the production of human IL-10 by established Th0, Th1, and Th2 T cell clones (TCC), T cell lines, and purified peripheral blood T cells. IL-12 synergized with anti-CD3 mAb, Con A, or IL-2 in inducing IL-10 production by Th0, Th1, and Th2 TCC and by T cell lines. This effect was dose dependent (from 0.1 to 50 U/ml) and associated with an increase of IL-10 mRNA transcription. As previously reported, IL-12 also enhanced IFN-gamma production by stimulated Th1 and Th0 TCC and, to a lesser extent, IL-4 production by stimulated Th0 and Th2 TCC. These observations were extended to peripheral blood T cells stimulated in the presence of exogenous IL-2. Moreover, using neutralizing anti-IL-2 Ab, we report that endogenous IL-2 produced by stimulated Th0 TCC could in part contribute to the effect of IL-12 on IL-10 and IL-4 production. In conclusion, IL-12 synergizes with IL-2 and other stimuli in inducing IL-4 and IL-10 production by T cells. This property may help to explain why IL-12 does not efficiently down-regulate an established Th2 response.
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Aarvak, Tanja, Martine Chabaud, Pierre Miossec, and Jacob B. Natvig. "IL-17 Is Produced by Some Proinflammatory Th1/Th0 Cells But Not by Th2 Cells." Journal of Immunology 162, no. 3 (February 1, 1999): 1246–51. http://dx.doi.org/10.4049/jimmunol.162.3.1246.
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Abstract IL-17 is defined as a proinflammatory cytokine and produced by activated CD4+ T cells. In rheumatoid arthritis synovial tissue, high levels of IL-17 contribute to IL-6 production by synoviocytes. The present study was performed to see whether Th cells that produce IL-17 are associated with the Th1, Th2, or Th0 subset. Thirty-three CD4+, αβ+ T cell clones were developed from synovial membranes and synovial fluid of rheumatoid arthritis patients. Thirteen clones were defined as Th1 since they produced IFN-γ but not IL-4, and four clones were defined as Th0 type that produced both IL-4 and IFN-γ. Sixteen clones were defined as Th2 since they produced high levels of IL-4 and/or IL-10 but not IFN-γ. IL-17 was measured in a bioassay, where IL-6 production from synoviocytes was a measurement for IL-17 activity in the presence and absence of blocking anti-IL-17 mAb. Three Th1 clones and two Th0 clones produced IL-17. In contrast, none of the sixteen Th2 clones analyzed produced IL-17. In addition, six Th2 clones were further cultured in conditions that induced a switch to Th1 type. Induction of this Th1 phenotype also led to production of IL-17 in two of these clones. The results demonstrate that some cells of the Th1/Th0 phenotype produce IL-17 but not cells of the Th2 phenotype. Thus, IL-17 may define a new subset of T cells, and IL-17 production appears to be a mechanism for Th1/Th0 cells, the most frequent Th subtype present in the rheumatoid synovium, to contribute to the local inflammatory reactions.
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Hamann, D., C. M. Hilkens, J. L. Grogan, S. M. Lens, M. L. Kapsenberg, M. Yazdanbakhsh, and R. A. van Lier. "CD30 expression does not discriminate between human Th1- and Th2-type T cells." Journal of Immunology 156, no. 4 (February 15, 1996): 1387–91. http://dx.doi.org/10.4049/jimmunol.156.4.1387.
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Abstract CD30 is a member of the TNF receptor superfamily that is commonly used as a marker for Hodgkin and Reed-Sternberg cells in Hodgkin's disease. More recently, it has been proposed that CD30 is preferentially up-regulated on Th2-type human T cells. We analyzed regulation of CD30 expression on both peripheral blood T cells and T cell clones. In short-term culture, CD30 expression could be induced on T cells by Ags that elicit Th2-type responses (Schistosoma haematobium, adult worm Ag, and Toxocaria canis, excretory/secretory Ag) and Th0-type responses (tetanus toxoid), as well as Th1-type responses (tuberculin purified protein derivative). Moreover, simultaneous measurement of membrane phenotype and cytokine production showed that CD30-expressing cells can produce IFN-gamma. Finally, within panels of randomly generated as well as Ag-specific T cell clones, CD30 expression was found on Th0-, Th2-, and Th1-type clones. We conclude that induction of CD30 on activated T cells is not related to differentiation in Th0-, Th1-, or Th2-type cells.
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Ye, Jing, Yuan Wang, Zhen Wang, Qingwei Ji, Ying Huang, Tao Zeng, Haiying Hu, Di Ye, Jun Wan, and Yingzhong Lin. "Circulating Th1, Th2, Th9, Th17, Th22, and Treg Levels in Aortic Dissection Patients." Mediators of Inflammation 2018 (September 6, 2018): 1–10. http://dx.doi.org/10.1155/2018/5697149.
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Background. Previous studies demonstrated that the subsets of CD4+ T helper (Th) cells are closely related to vascular diseases, including atherosclerosis and hypertension. This study is aimed at investigating the circulating Th1, Th2, Th9, Th17, Th22, and Treg levels in aortic dissection (AD) patients. Methods. Blood samples from AD (n=56) and non-AD (NAD, n=24) patients were collected, and the circulating levels of Th1, Th2, Th9, Th17, Th22, and Treg cells and their transcription factors and functional cytokines were measured by flow cytometric analysis, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assays, respectively. In addition, the human aortic vascular smooth muscle cells (HASMCs) were treated with saline, angiotensin II (Ang II), or plasma from AD patients. Results. Compared with the levels in the NAD group, the Th1, Th9, Th17, Th22, and their transcription factor levels were increased and the Th2, Treg, and their transcription factor levels exhibited a decreasing trend in AD patients. In addition, higher IFN-γ, IL-9, IL-17, and IL-22 levels and lower IL-4 and IL-35 levels were observed in AD patients. Simple linear regression analysis and binary logistic regression analysis suggested that Th1/IFN-γ, IL-9, Th17/IL-17, and Th22/IL-22 positively regulated the occurrence of AD, while Th2/IL-4 and Treg/IL-35 negatively regulated the occurrence of AD. Plasma from AD patients further increased Bax mRNA levels but decreased Bcl2 and α-SMA mRNA levels in Ang II-treated HASMCs. Conclusions. Changes in Th1, Th2, Th9, Th17, Th22, and Treg activity are associated with the onset of AD. Different subsets of CD4+ T cells play different roles in the presence of AD.
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Romagnani, Sergio. "Th1/Th2 Cells." Inflammatory Bowel Diseases 5, no. 4 (November 1999): 285–94. http://dx.doi.org/10.1097/00054725-199911000-00009.
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Romagnani, Sergio. "Th1/Th2 cells." Inflammatory Bowel Diseases 5, no. 4 (April 18, 2007): 285–94. http://dx.doi.org/10.1002/ibd.3780050410.
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Rasheed, Mustafa N., Bharath Sreekumar, Sol C. Moon, Michael Duane Powell, Kaitlin Read, and Kenneth J. Oestreich. "Novel roles for the Ikaros zinc finger transcription factor Eos in regulating TH2 differentiation." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 124.6. http://dx.doi.org/10.4049/jimmunol.202.supp.124.6.
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Abstract CD4+ T cells differentiate in response to specific cytokine environments that induce the activation of STAT transcription factors and, ultimately, cell-specific gene profiles. The differentiation of TH2 cells requires the cytokines IL-4 and IL-2, which signal via the activation of STAT6 and STAT5, respectively. Interestingly, signaling via the IL-2/STAT5 axis is also required for the differentiation of the TH1 cell type. Our lab recently found that IL-2 signaling induces expression of the Ikaros Zinc Finger (IkZF) transcription factor Eos (Ikzf4) in TH1 cells, and that Eos positively regulates TH1-specific gene expression. Given the requirement for IL-2 signaling in TH2 development, we hypothesized that Eos may also play a role in TH2 differentiation. Indeed, we found that Eos expression was increased in TH2 cells at both the transcript and protein level as compared to TH0, TH1, and TFH-like cells. We also found that Eos knockdown resulted in a significant decrease in the expression of the canonical TH2 genes Il4 and Il13. When we cultured Eos-deficient cells in TH2-polarizing conditions, we similarly observed a decrease in Il4 and Il13 expression, as well as reduced expression of Il2ra and Il2rb. Eos-deficient TH2 cells also displayed decreased expression of Prdm1, the gene encoding Blimp-1, which represses the expression of alternative T helper cell gene programs in TH2 cells. Taken together, these data support a novel, positive role for Eos in the regulation of the TH2 gene program.
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Vicenzi, Elisa, Paola Panina Bordignon, Priscilla Biswas, Andrea Brambilla, Chiara Bovolenta, Manuela Cota, Francesco Sinigaglia, and Guido Poli. "Envelope-Dependent Restriction of Human Immunodeficiency Virus Type 1 Spreading in CD4+ T Lymphocytes: R5 but Not X4 Viruses Replicate in the Absence of T-Cell Receptor Restimulation." Journal of Virology 73, no. 9 (September 1, 1999): 7515–23. http://dx.doi.org/10.1128/jvi.73.9.7515-7523.1999.
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ABSTRACT The human immunodeficiency virus (HIV) replicates in activated CD4+ T lymphocytes. However, only CD4+ Th2 and Th0, but not Th1, CD4+ T-cell clones have been reported to efficiently support HIV-1 replication. This dichotomous pattern was further investigated in the present study in Th1, Th2, or Th0 cell lines derived from umbilical human cord blood and in T-cell clones obtained from the peripheral blood mononuclear cells (PBMC) of healthy adults. Both primary and laboratory-adapted HIV-1 strains with CCR5 as the exclusive entry coreceptor (R5 viruses) efficiently replicated in Th1, Th2, and Th0 cells. In sharp contrast, CXCR4-dependent (X4) viruses poorly replicated in both polarized and unpolarized CD4+ T cells, including adults’ PBMC infected several days after mitogenic stimulation. Unlike the X4 HIV-1NL4-3, a chimera in which the env gene had been replaced with that of the R5 HIV-1NL(AD8), efficiently replicated in both Th1 and Th2 cells. This X4-dependent restriction of HIV replication was not explained by either the absence of functional CXCR4 on the cell surface or by the inefficient viral entry and reverse transcription. T-cell receptor stimulation by anti-CD3 monoclonal antibodies fully rescued X4 HIV-1 replication in both Th1 and Th2 cells, whereas it did not alter the extent and kinetics of R5 HIV-1 spreading. Thus, R5 HIVs show a replicative advantage in comparison to X4 viruses in their ability to efficiently propagate among suboptimally activated T lymphocytes, regardless of their polarized or unpolarized functional profiles. This observation may help to explain the absolute predominance of R5 HIVs over X4 viruses observed after viral transmission and during early-stage disease.
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Tatsumi, Tomohide, Lisa S. Kierstead, Elena Ranieri, Loreto Gesualdo, Francesco P. Schena, James H. Finke, Ronald M. Bukowski, et al. "Disease-associated Bias in T Helper Type 1 (Th1)/Th2 CD4+ T Cell Responses Against MAGE-6 in HLA-DRB1*0401+ Patients With Renal Cell Carcinoma or Melanoma." Journal of Experimental Medicine 196, no. 5 (August 26, 2002): 619–28. http://dx.doi.org/10.1084/jem.20012142.
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T helper type 1 (Th1)-type CD4+ antitumor T cell help appears critical to the induction and maintenance of antitumor cytotoxic T lymphocyte (CTL) responses in vivo. In contrast, Th2- or Th3/Tr-type CD4+ T cell responses may subvert Th1-type cell-mediated immunity, providing a microenvironment conducive to disease progression. We have recently identified helper T cell epitopes derived from the MAGE-6 gene product; a tumor-associated antigen expressed by most melanomas and renal cell carcinomas. In this study, we have assessed whether peripheral blood CD4+ T cells from human histocompatibility leukocyte antigens (HLA)-DRβ1*0401+ patients are Th1- or Th2-biased to MAGE-6 epitopes using interferon (IFN)-γ and interleukin (IL)-5 enzyme-linked immunospot assays, respectively. Strikingly, the vast majority of patients with active disease were highly-skewed toward Th2-type responses against MAGE-6–derived epitopes, regardless of their stage (stage I versus IV) of disease, but retained Th1-type responses against Epstein-Barr virus– or influenza-derived epitopes. In marked contrast, normal donors and cancer patients with no current evidence of disease tended to exhibit either mixed Th1/Th2 or strongly Th1-polarized responses to MAGE-6 peptides, respectively. CD4+ T cell secretion of IL-10 and transforming growth factor (TGF)-β1 against MAGE-6 peptides was not observed, suggesting that specific Th3/Tr-type CD4+ subsets were not common events in these patients. Our data suggest that immunotherapeutic approaches will likely have to overcome or complement systemic Th2-dominated, tumor-reactive CD4+ T cell responses to provide optimal clinical benefit.
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Kasatskaya, Sofya A., Kristin Ladell, Evgeny S. Egorov, David A. Price, and Dmitriy Chudakov. "T cell receptor repertoire features display universal rules for selection and plasticity in the functional CD4 T cell subsets." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 230.9. http://dx.doi.org/10.4049/jimmunol.204.supp.230.9.
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Abstract Helper T cell choice of functional subset may depend on the mode and strength of T cell receptor interaction with peptide-MHC complex on antigen presenting cells. However, the extent, complexity, and homogeneity of this influence of TCR structure on the selection into a functional subset, as well as further stability of acquired clonal programs remain poorly studied. Here we present the first analysis of deep sequenced T-cell receptor repertoires of the eight effector CD4 T cell subsets (Th1, Th2, Th2a, Th17, Th1-17, Th22, Treg, and Tfh) from peripheral blood of 5 healthy donors, revealing unexpectedly prominent, multivariate subset-specific differences that are highly reproducible across unrelated donors. Similar analysis performed for the sorted naive CD4 T cell subsets showed that specific TCR features of Tregs (short and strongly interacting CDR3 region) are rooted in thymic selection, while differences between other subsets accumulate later upon T cell functional engagement. We next provide the first deep analysis of the plasticity of human effector CD4 subsets ex vivo. We demonstrate high plasticity within Th17 and Th22 functional subsets and prominent clonal exchange of both Th17 and Th22 with Th2. Th1-17 subset shares clones with Th1 but not with the Th17 subset. Finally, we investigate relative publicity of effector CD4 subset repertoires across donors. We reveal high publicity of Treg and Tfh, and high privacy of Th22 and Th2a repertoires, which corresponds to the number of added N-nucleotides for these subsets, suggesting their earlier fetal and evolutionary origin. Altogether, we provide the first detailed picture of distinct repertoire features, plasticity, and publicity of helper CD4 T cell subsets.
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Wen, Li, Domingo F. Barber, William Pao, F. Susan Wong, Michael J. Owen, and Adrian Hayday. "Primary γδ Cell Clones Can Be Defined Phenotypically and Functionally as Th1/Th2 Cells and Illustrate the Association of CD4 with Th2 Differentiation." Journal of Immunology 160, no. 4 (February 15, 1998): 1965–74. http://dx.doi.org/10.4049/jimmunol.160.4.1965.
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Abstract The division of CD4+ αβ T cells into Th1 and Th2 subsets has become an established and important paradigm. The respective activities of these subsets appear to have profound effects on the course of infectious and autoimmune diseases. It is believed that specific programs of differentiation induce the commitment of an uncommitted Th0 precursor cell to Th1 or Th2. A component of these programs is hypothesized to be the nature of MHC-peptide antigen presentation to the αβ T cell. It has heretofore remained uncertain whether a Th1/Th2 classification likewise defines, at the clonal level, γδ T cells. Such cells do not, as a general rule, express either CD4 or CD8αβ, and they do not commonly recognize peptide-MHC. In this report, γδ cell clones are described that conform strikingly to the Th1/Th2 classification, both by cytokine expression and by functional activities of the clones in vitro and in vivo. Provocatively, both the γδ cell clones and primary γδ cells in vivo showed a strong association of the Th2 phenotype with CD4 expression. These results are discussed with regard to the immunoregulatory role that is increasingly emerging for γδ cells.
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Desmedt, Marjory, Pieter Rottiers, Hans Dooms, Walter Fiers, and Johan Grooten. "Macrophages Induce Cellular Immunity by Activating Th1 Cell Responses and Suppressing Th2 Cell Responses." Journal of Immunology 160, no. 11 (June 1, 1998): 5300–5308. http://dx.doi.org/10.4049/jimmunol.160.11.5300.
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Abstract Differentiation of naive CD4+ T cells (Th0) into Th1 or Th2 cells determines whether antigen will raise a cellular or a humoral immune response. The maturation pathway chosen by the Th0 cell is often decisive for the outcome of disease and depends among others on the (co-)stimulatory attributes of the APC and the nature and abundance of cytokines provided by the APC and the microenvironment. In this study, we used macrophages, loaded ex vivo with antigen, for inciting Th0 activation and differentiation in vivo. The macrophages were derived from a clonal, immortalized population that both functionally and phenotypically expressed features characteristic of mature macrophages. Injection into syngeneic mice of IFN-γ-treated, Ag-loaded macrophages induced a primary T cell response, indicated by the occurrence of a proliferative response in vitro after restimulation of splenocytes with Ag. Analysis of the accompanying cytokine secretion revealed high numbers of IFN-γ-producing Th1 cells and only a few IL-4-secreting Th2 cells. This dominance of Th1 cells had functional implications, reflected in the high titer of Th1 cell-dependent IgG2 Abs and the absence of IgG1, characteristic of humoral immunity. Moreover, administration of Ag-loaded macrophages to mice with an ongoing Th1/Th2 response resulted in a complete suppression of IgG1 production, whereas IgG2 levels remained unaffected. These results demonstrate that macrophages exert APC activity in the organism, strongly skew primary responses to cellular immunity, and in addition suppress an already generated Th2-dependent humoral response, thus characterizing these cells as Th1-oriented APC.
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Dhib-Jalbut, S., M. Chen, K. Henschel, D. Ford, K. Costello, and H. Panitch. "Effect of combined IFNb-1a and glatiramer acetate therapy on GA-specific T-cell responses in multiple sclerosis." Multiple Sclerosis Journal 8, no. 6 (December 2002): 485–91. http://dx.doi.org/10.1191/1352458502ms862oa.
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The combined treatment with interferon (IFN) and glatiramer acetate (GA) is of current interest in multiple sclerosis (MS). The therapeutic effect of GA in MS is believed to be mediated by GA-specific Th2 cells. IFN has a significant anti-proliferative effect on GA-induced lymphoproliferation in vitro. Therefore, we examined the possibility that IFN may interfere with the generation and phenotype of GA T-cell responses in MS patients receiving combined therapy. Sixty-six GA-specific T-cell lines (TCL) were generated ex vivo from five MS patients enrolled in an open-label clinical trial of combined IFN/GA treatment. Controls included 83 pretreatment and 131 on-treatment GA-TCL from 11 MS patients treated with GA only, and five GA-TCL generated from four patients receiving IFN -1a monotherapy. IFNg and IL-5 (markers of Th1 and Th2 responses, respectively) were assayed by ELISA in GA-TCL supernatants. Th1/Th2 bias was defined by the IFNg/IL-5 level ratio (> 2=Th1 bias, <0.5=Th2 bias, and 0.5- 2=Th0 bias). The frequency with which GA-reactive TCL were generated was 37.0% for the patients in the combination trial compared to 33.3% in the patients receiving GA alone. The mean stimulation index of the GA-TCL was 8.41 (range 2-42) for the combination compared to a mean of 6.29 (range 2-37) for the GA-treated group - a nonsignificant difference. Mean GA-TCL IFNg production was significantly lower in all treatment groups compared to pretreatment. IL-5 levels were enhanced in all treatment groups compared to pretreatment levels, but the change was not statistically significant. The Th1/Th0/Th2 distribution of GA-TCL was 7%/30%/63% for the GA+IFN group, 8%/9%/83% for the GA group, compared to 48%/21%/31% pre-GA treatment. All five GA-TCL from the IFN -1a monotherapy patients were Th2-biased. We conclude that IFN -1a does not affect the generation of GA-reactive T cells in vivo. Although more Th0 GA-TCL occurred with combination therapy than with GA treatment alone, both groups shared an overall Th2 bias. Therefore, we speculate that combined therapy is unlikely to reduce the efficacy of GA treatment in MS.
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Mariotti, Jacopo, Jason Foley, Todd Borenstein, Soo Han, and Daniel H. Fowler. "Rapamycin Generated Murine Th2/Tc2 Cells Potently Abrogate Fully MHC-Mismatched Hematopoietic Stem Cell (HSC) Graft Rejection." Blood 106, no. 11 (November 16, 2005): 192. http://dx.doi.org/10.1182/blood.v106.11.192.192.
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Abstract We previously showed that costimulated Th2/Tc2 cells abrogate graft rejection. In recent experiments, we found that ex vivo rapamycin generates Th2 cells (Th2R cells) that more potently prevent GVHD relative to control Th2 cells. We thus hypothesized that rapamycin may improve the ability of Th2/Tc2 cells to abrogate graft rejection. To test this hypothesis, we utilized a recently defined model of rejection involving lethal host irradiation and subsequent quantitative host T cell addback [B6(H-2b) into BALB/c(H-2d), TBI:10.5 Gy; 0.1x10^6 host T cell addback]. To generate stem-cell enriched allografts, donor mice were treated with G-CSF (5 microgram/d for 5 d) and resultant spleen cells were expanded for 6 d in rhTPO, rmSCF and rhFLT3L: relative to input cells, the final product was T cell depleted (%CD3 reduced from 9.7±0.6% to 0.4±0.03%) and stem-cell enriched by KLS analysis (%c-kit+Lin-Sca-1+ increased from 5.7±1.8% to 49.08±2.8%) and by functional analysis (%side population increased from 0.24±0.04% to 1.7±0.2). In an initial experiment that did not involve host T cell addback, we determined that 10x10^6 of the HSC product was radioprotective in 100% of recipients (10/10 subjects, 90 d follow-up) and yielded 100% donor chimerism without clinical GVHD. To generate donor Th2/Tc2 and Th2/Tc2R cells, donor T cells were costimulated with anti-CD3/CD28 coated beads and expanded in media supplemented with rmIL-4, rhIL-2, rhIL-7 either without or with high dose rapamycin (10 micromolar). Host-vs-graft (HVG) responses were quantified at d 5 post transplant by the following method: (a) spleen cell harvest and enumeration; (b) 24 h host (syngeneic) or donor (allogeneic) dendritic cell stimulation; (c) cell-surface flow cytometry with anti-CD4, anti-CD8 and anti-host (H-2d) antibodies; (d) Miltenyi IFN-gamma cytokine capture flow cytometry; and (e) calculation of absolute number of host anti-donor alloreactive CD4+ and CD8+ T cells per spleen. HSC transfer without Th2/Tc2 cells induced robust CD4- and CD8-mediated HVG responses (Fig.1, cohort 2>cohort 1; p<0.001). HSC transfer augmented with donor Th2/Tc2R cells fully abrogated HVG responses; in marked contrast, HSC transfer augmented with control Th2/Tc2 cells only partially reduced HVG responses. Rapamycin generated Th2/Tc2 cells were more potent than control Th2/Tc2 cells with respect to abrogation of both CD4- and CD8-mediated HVG responses (p<0.05). The mechanism of Th2/Tc2R cells abrogation of HVG responses involved both CD4+Th2R and CD8+Tc2R cell components, and did not require IL-4, perforin, or fas ligand. At day 90 post transplant, Th2/Tc2R cell recipients had nominal GVHD (<5% weight loss) and consistent alloengraftment (>99% chimerism, 9 of 10 recipients; rejection, 1 of 10 recipients); in marked contrast, control Th2/Tc2 cell recipients had either graft rejection (9 of 10 recipients) or mixed chimerism (1 of 10 recipients). In conclusion, ex vivo rapamycin generates donor Th2/Tc2 cells that potently abrogate HVG responses and HSC graft rejection through a mechanism that involves CD4+Th2 and CD8+Tc2 cells and non-classical molecular effectors. Figure 1: Donor Th2/Tc2R Cell Modulation of HVG Responses. B6-into-BALB/c transplantation was performed (10 x 106 donor HSC; 10 x 106 donor T cells; 1 x 106 host T cells; 1050 cGy XRT; n=10 mice per cohort). Mice were killed at d 5 post-SCT, and absolute number of host anti-donor alloreactive CD4 and CD8 Cells was determined by IFN-gamma cytokine capture flow cytometry. * indicates p<0.05 and ** indicates p<0.001 (student’s t-test); each cohort compared with cohort #2. Abbreviations: KO, Knockout, PFN, perfocin, FASL, fas ligand. Figure 1:. Donor Th2/Tc2R Cell Modulation of HVG Responses. B6-into-BALB/c transplantation was performed (10 x 106 donor HSC; 10 x 106 donor T cells; 1 x 106 host T cells; 1050 cGy XRT; n=10 mice per cohort). Mice were killed at d 5 post-SCT, and absolute number of host anti-donor alloreactive CD4 and CD8 Cells was determined by IFN-gamma cytokine capture flow cytometry. * indicates p<0.05 and ** indicates p<0.001 (student’s t-test); each cohort compared with cohort #2. Abbreviations: KO, Knockout, PFN, perfocin, FASL, fas ligand.
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Webb, LM, and M. Feldmann. "Critical role of CD28/B7 costimulation in the development of human Th2 cytokine-producing cells." Blood 86, no. 9 (November 1, 1995): 3479–86. http://dx.doi.org/10.1182/blood.v86.9.3479.bloodjournal8693479.
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CD28 is a major costimulatory signal receptor for T cells. We have used human naive CD4+ cells from cord blood to analyze the effect of the CD28/B7 costimulatory pathway on development of T helper (Th) subsets. We show that CD28 costimulation is critical for development of the Th2 cytokine-producing cells and that in the absence of CD28 costimulation, cells are not primed to produce Th2 cytokines and consequently “default” to the Th1 subset, independent of the presence of exogenous cytokines. After CD28 costimulation, cells differentiate into a subset that produces Th2 cytokines. However, further CD28 costimulation is not required to maintain Th2 cytokine production. We conclude that D28 costimulation is critical for the development of Th0 and Th2 subsets, but not for the maintenance of cytokine production.
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Saito, S., N. Tsukaguchi, T. Hasegawa, T. Michimata, H. Tsuda, and N. Narita. "Distribution of Th1, Th2, and Th0 and the Th1/Th2 Cell Ratios in Human Peripheral and Endometrial T Cells." American Journal of Reproductive Immunology 42, no. 4 (October 1999): 240–45. http://dx.doi.org/10.1111/j.1600-0897.1999.tb00097.x.
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Lohoff, M. "Das Th1/Th2-Konzept." Allergologie 25, no. 07 (July 1, 2002): 398–402. http://dx.doi.org/10.5414/alp25398.
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Stevens, David A. "Th1/Th2 in aspergillosis." Medical Mycology 44, s1 (January 2006): 229–35. http://dx.doi.org/10.1080/13693780600760773.
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Dechene, Lucy. "TH1/TH2 immune response." Journal of Allergy and Clinical Immunology 110, no. 3 (September 2002): 539–40. http://dx.doi.org/10.1067/mai.2002.127436.
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Romagnani, Sergio. "The Th1/Th2 paradigm." Immunology Today 18, no. 6 (June 1997): 263–66. http://dx.doi.org/10.1016/s0167-5699(97)80019-9.
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Romagnani, S., M. Kapsenberg, A. Radbruch, and L. Adorini. "Th1 and Th2 cells." Research in Immunology 149, no. 9 (November 1998): 871–73. http://dx.doi.org/10.1016/s0923-2494(99)80016-9.
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Dong, Chen, and Richard A. Flavell. "Th1 and Th2 cells." Current Opinion in Hematology 8, no. 1 (January 2001): 47–51. http://dx.doi.org/10.1097/00062752-200101000-00009.
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Fishman, Michael A., and Alan S. Perelson. "Th1/Th2 Cross Regulation." Journal of Theoretical Biology 170, no. 1 (September 1994): 25–56. http://dx.doi.org/10.1006/jtbi.1994.1166.
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Young, H. A., P. Ghosh, J. Ye, J. Lederer, A. Lichtman, J. R. Gerard, L. Penix, C. B. Wilson, A. J. Melvin, and M. E. McGurn. "Differentiation of the T helper phenotypes by analysis of the methylation state of the IFN-gamma gene." Journal of Immunology 153, no. 8 (October 15, 1994): 3603–10. http://dx.doi.org/10.4049/jimmunol.153.8.3603.
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Abstract Th1 and Th2 CD4+ T cell clones have been defined by their ability to produce different lymphokines. However, the processes by which CD4+ T cells differentially regulate lymphokine gene expression have not been well defined. In this report, we demonstrate that the methylation status of a CpG dinucleotide contained within a TATA proximal regulatory element of the IFN-gamma promoter correlates with the transcription of the gene. In murine Th1 clones and two human CD4+ Th0 clones, this site is either completely or partially hypomethylated, whereas in murine Th2 clones this site is > 98% methylated. Treatment of murine Th2 clones with 5-azacytidine, an agent that inhibits methylation of the DNA, converts these cells to IFN-gamma producers. Additional targets for methylation outside the transcriptional control regions of the IFN-gamma genetic locus were found to be hypomethylated in Th2 cells but not in Th1 cells. Electrophoretic mobility shift assays (EMSA) revealed at least five distinct protein-DNA complexes that are formed with an oligonucleotide containing the IFN-gamma promoter TATA proximal regulatory element, and in vitro methylation of this site results in a loss of these three complexes. Furthermore, a comparison of nuclear extracts prepared from Th1 and Th2 clones revealed that the EMSA patterns were qualitatively similar but differed quantitatively. In addition, transient transfection of a murine IFN-gamma promoter-chloramphenicol acetyl transferase (CAT) gene construct into both Th1 and Th2 clones produced CAT activity that was not inducible by anti-CD3, indicating that hypomethylation per se of the promoter alone is not sufficient for inducible gene expression.
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DE ALMEIDA, MARCOS C., and HELMAR N. MOREIRA. "A MATHEMATICAL MODEL OF IMMUNE RESPONSE IN CUTANEOUS LEISHMANIASIS." Journal of Biological Systems 15, no. 03 (September 2007): 313–54. http://dx.doi.org/10.1142/s0218339007002209.
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The TH1/TH2 paradigm has been largely used in the interpretation of several diseases, particularly in leishmaniasis. As far as we know there is no mathematical description of this model related to leishmaniasis. We have extended and modified a previous published set of equations1in order to adapt it to leishmanial disease particularities. The main modifications were: (1) the analysis of logistic and exponential parasite growth curves, (2) the assumption of the TH2 arm of the immune response having a positive action on parasite growth. The set of three simultaneous differential equations describing the TH1 arm, TH2 arm and parasite growth were analyzed for conditions of existence and stability of the solutions.Stable solutions valid for the logistic and exponential parasite growth models, with its possible clinical correlations, were obtained in the following situations: (1) parasite and TH2 extinction [TH1 cure], (2) parasite extinction and TH1/TH2 co-existence [TH1/TH2 cure], (3) TH1 and parasite co-existence, TH2 extinction [stable TH1 infection], and (4) TH1, TH2 and parasite co-existence [stable TH1/TH2 infection]. TH2 and parasite co-existence associated to TH1 extinction [stable TH2 infection] was obtained only with the logistic growth model. The model also provides an alternative hypothesis for TH1 bias in resistant mice and emphazises the importance of natural immunity for the existence of chronic states.
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Müller, Kerstin, Susanne Bischof, Frank Sommer, Michael Lohoff, Werner Solbach, and Tamás Laskay. "Differential Production of Macrophage Inflammatory Protein 1γ (MIP-1γ), Lymphotactin, and MIP-2 by CD4+ Th Subsets Polarized In Vitro and In Vivo." Infection and Immunity 71, no. 11 (November 2003): 6178–83. http://dx.doi.org/10.1128/iai.71.11.6178-6183.2003.
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ABSTRACT Due to differential expression of chemokine receptors, the Th1 and Th2 subsets of CD4+ T cells differ in their migratory responses to chemokines. These differences in the migration patterns are likely to play a role in the initiation and regulation of Th1 and Th2 immune responses, inflammatory processes, and T-cell-mediated pathology. In the present study we evaluated the role of activated Th cells as producers of chemokines. Three different sources of murine Th cells were used, i.e., long-term-cultured Th1 and Th2 cell clones, Th1 and Th2 cells differentiated from naïve CD4+ spleen and lymph node cells in vitro, and Th1 and Th2 subsets polarized in vivo using a murine experimental Leishmania major infection model. Following stimulation with anti-CD3, macrophage inflammatory protein 1γ (MIP-1γ) and lymphotactin were produced selectively by Th1 cells but not by Th2 cells. In contrast, only Th2 cells produced MIP-2. The possible biological relevance of these data was substantiated by the finding that in vivo-polarized Th1 cells, but not Th2 cells, produced MIP-1γ and lymphotactin while in vivo-polarized Th2 cells secreted MIP-2. The above data demonstrate that Th1 and Th2 cells differ in their ability to produce chemokines, suggesting that Th1 and Th2 subsets differentially contribute to recruitment of cells into inflammatory foci.
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Piccinni, M. P., E. Maggi, and S. Romagnani. "Role of hormone-controlled T-cell cytokines in the maintenance of pregnancy." Biochemical Society Transactions 28, no. 2 (February 1, 2000): 212–15. http://dx.doi.org/10.1042/bst0280212.
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Human CD4 T helper lymphocytes can be subdivided into at least three distinct functional subsets on the basis of their cytokine secretion profiles. One type of CD4+ lymphocyte, T helper 1 (Th1), produces interferon (IFN)-γ and tumour necrosis factor β, a second type (Th2) produces interleukin (IL)-4 and IL-5 and a third type (Th0) produces both Th1 and Th2 cytokines. The apparent paradox that embryos are not rejected by the maternal immune system despite the presence of paternal MHC histocompatibility antigens has been explained in mice by a Th2 switch at the level of the materno-fetal interface. We showed that some hormones enhanced during pregnancy can affect the development of Th1 and Th2 responses. Indeed, we found that progesterone promotes the production of IL-4 and IL-5, whereas relaxin promotes the production of IFN-γ by T-cells. In addition, we showed that leukaemia inhibitory factor (LIF), which is essential for embryo implantation, associates with Th2 cells and is upregulated by IL-4 and progesterone. We also showed that LIF is down-regulated by Th1 inducers [IL-12, IFN-γ and IFN-α]. Further-more, we found a decreased production of LIF, IL-4 and IL-10 by decidual T-cells in women with unexplained recurrent abortions in comparison with women with normal gestation at the moment of voluntary abortion. The decreased production of LIF, IL-4 and IL-10 was not found in peripheral-blood T-cells. These results suggest that the local production of LIF and/or Th2 cytokines may contribute to the maintenance of pregnancy.
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Lederer, J. A., J. S. Liou, M. D. Todd, L. H. Glimcher, and A. H. Lichtman. "Regulation of cytokine gene expression in T helper cell subsets." Journal of Immunology 152, no. 1 (January 1, 1994): 77–86. http://dx.doi.org/10.4049/jimmunol.152.1.77.
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Abstract We have examined the transcriptional regulation of the Th1-specific IL-2 gene and the Th2-specific IL-4 gene by transient transfection of promoter-chloramphenicol acetyl transferase (CAT) constructs into T cell clones and by electrophoretic mobility shift assays. Transfection of the Th2 clone D10.G4 with IL-4 promoter-CAT constructs demonstrated anti-CD3 inducible IL-4 promoter activity. In contrast, CAT constructs containing murine IL-2 promoter sequences were not inducible in D10.G4 cells. Transfection analyses in the Th1 clone D1.1 demonstrated inducible IL-2 promoter activity but no IL-4 promoter activity. Electrophoretic mobility shift assays using well-defined regulatory elements in the murine IL-2 gene promoter showed that anti-CD3 stimulation of Th2 clones failed to induce a characteristic increase in the ratio of p65-p50:p50-p50 NF-kappa B binding complexes in the nucleus that did occur in IL-2-producing clones. In addition, other protein complexes with NF-kappa B binding sequences were seen using lysates from Th1 and Th0 cells but not Th2 cells. Thus, expression of the promoter-CAT constructs directly correlates with endogenous IL-2 and IL-4 gene expression in Th1 and Th2 clones, confirming that the differential expression of IL-2 and IL-4 genes in these T cells is transcriptionally controlled. Furthermore, the lack of IL-2 transcription in activated Th2 cells is associated with the failure to generate required IL-2 gene promoter binding proteins, particularly NF-kappa B in the nucleus.
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Sornasse, T., P. V. Larenas, K. A. Davis, J. E. de Vries, and H. Yssel. "Differentiation and stability of T helper 1 and 2 cells derived from naive human neonatal CD4+ T cells, analyzed at the single-cell level." Journal of Experimental Medicine 184, no. 2 (August 1, 1996): 473–83. http://dx.doi.org/10.1084/jem.184.2.473.
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The development of CD4+ T helper (Th) type 1 and 2 cells is essential for the eradication of pathogens, but can also be responsible for various pathological disorders. Therefore, modulation of Th cell differentiation may have clinical utility in the treatment of human disease. Here, we show that interleukin (IL) 12 and IL-4 directly induce human neonatal CD4- T cells, activated via CD3 and CD28, to differentiate into Th1 and Th2 subsets. In contrast, IL-13, which shares many biological activities with IL-4, failed to induce T cell differentiation, consistent with the observation that human T cells do not express IL-13 receptors. Both the IL-12-induced Th1 subset and the IL-4-induced Th2 subset produce large quantities of IL-10, confirming that human IL-10 is not a typical human Th2 cytokine. Interestingly, IL-4-driven Th2 cell differentiation was completely prevented by an IL-4 mutant protein (IL-4.Y124D), indicating that this molecule acts as a strong IL-4 receptor antagonist. Analysis of single T cells producing interferon gamma or IL-4 revealed that induction of Th1 cell differentiation occurred rapidly and required only 4 d of priming of the neonatal CD4+ T cells in the presence of IL-12. The IL-12-induced Th1 cell phenotype was stable and was not significantly affected when repeatedly stimulated in the presence of recombinant IL-4. In contrast, the differentiation of Th2 cells occurred slowly and required not only 6 d of priming, but also additional restimulation of the primed CD4+ T cells in the presence of IL-4. Moreover, IL-4-induced Th2 cell phenotypes were not stable and could rapidly be reverted into a population predominantly containing Th0 and Th1 cells, after a single restimulation in the presence of IL-12. The observed differences in stability of IL-12- and IL-4-induced human Th1 and Th2 subsets, respectively, may have implications for cytokine-based therapies of chronic disease.
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Saito, Sakai, Sasaki, Tanebe, Tsuda, and Michimata. "Quantitative analysis of peripheral blood Th0, Th1, Th2 and the Th1:Th2 cell ratio during normal human pregnancy and preeclampsia." Clinical & Experimental Immunology 117, no. 3 (September 1999): 550–55. http://dx.doi.org/10.1046/j.1365-2249.1999.00997.x.
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Adair, Patrick, Yongchan Kim, Kathleen Pratt, and David Scott. "Engineered FVIII-specific human CD4 T cells: does TCR avidity modulate T-helper phenotypes? (IRC7P.425)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 128.6. http://dx.doi.org/10.4049/jimmunol.194.supp.128.6.
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Abstract We recently demonstrated that expanded human CD4 T cells can be transduced to express TCRs specific for a given epitope. These cells proliferate and secrete cytokines in response to their cognate peptide/MHC. Herein, we examined whether TCR- transduced cells could be skewed to different T-helper subsets, or alternatively if previously skewed T cells could be modulated after transduction. Two HLA DR1-restricted TCRs were cloned from Th2 and Th17/Th1-type CD4+ T-cell clones specific for a coagulation factor VIII peptide (pC2). Engineered CD4+ T cells expressing these TCRs exhibited different proliferation kinetics during titration with pC2. All pC2-stimulated cells expressed IFN-g, IL-4, and IL-2 intracellularly but did not express cytokine signatures characteristic of their parental Th2 and Th17/Th1 clones. CD45RA+ and CD45RA- T cells were skewed to Th1, Th2 or Th17 and then transduced with each of the 2 TCRs. The higher-avidity TCR cells that were skewed to Th2 and then stimulated with low [pC2] maintained a Th2 cytokine signature, whereas the same cells stimulated with higher [pC2] expressed lower levels of IL-4 and GATA3. In contrast, Th1, Th17 and Th0-skewed cells transduced with the same TCR expressed their respective cytokines at all pC2 doses. Differences between the low-avidity TCR-engineered cells were less pronounced. These studies will inform our strategies for designing novel T-helper cellular therapies.
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Yoshino, S., H. Hayashp, S. Taneda, H. Takano, M. Sagai, and Y. Mori. "Effects of Diesel Exhaust Particle Extracts on TH1 and TH2 Immune Responses in Mice." International Journal of Immunopathology and Pharmacology 15, no. 1 (January 2002): 13–18. http://dx.doi.org/10.1177/039463200201500102.
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The present study was undertaken to investigate the effects of extracts of diesel exhaust particles (DEP) on Th1 and Th2 immune responses. In order to separate compounds from DEP different in hydrophobicity, a single DEP sample was consecutively extracted with hexane (HEX-DEP), benzene (BEN-DEP), dichloromethane (DIC-DEP), methanol (MET-DEP), and 1M ammonia (AMM-DEP). The last unextracted residue (UNE-DEP) was also used to test its effect on immune responses. To immunize mice, hen egg lysozyme (HEL) was injected i.p. (day 0). Varying doses of DEP, each DEP extract, and UNE-DEP were intranasally administered every 2 days from days 0 to 18. Anti-HEL IgG2a antibodies in sera and IFN-g secreted from spleen cells were measured as an indicator of Th1 immune responses, while anti-HEL IgG1 antibodies and IL-4 as that of Th2 responses. The results showed that treatment with DEP and DIC-DEP increased both Th1 and Th2 responses to HEL. UNE-DEP facilitated Th1 but not Th2 responses, while MET- and AMM-DEP administration was followed by enhancement of Th2 but not Th1 responses. Neither HEX- nor BEN-DEP modulated Th1 as well as Th2 responses. These results suggest that DEP contain various compounds different in hydrophobicity which may affect both Th1 and Th2, Th1 but not Th2, and Th2 but not Th1 immune responses.
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Lafaille, Juan J., Fabienne Van de Keere, Albert L. Hsu, Jody L. Baron, Werner Haas, Cedric S. Raine, and Susumu Tonegawa. "Myelin Basic Protein–specific T Helper 2 (Th2) Cells Cause Experimental Autoimmune Encephalomyelitis in Immunodeficient Hosts Rather than Protect Them from the Disease." Journal of Experimental Medicine 186, no. 2 (July 21, 1997): 307–12. http://dx.doi.org/10.1084/jem.186.2.307.
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Chronic inflammatory autoimmune diseases such as multiple sclerosis, diabetes, and rheumatoid arthritis are caused by CD4+ Th1 cells. Because Th2 cells antagonize Th1 cell functions in several ways, it is believed that immune deviation towards Th2 can prevent or cure autoimmune diseases. Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease used as a model for multiple sclerosis. Using an adoptive transfer system we assessed the role of Th1 and Th2 cells in EAE. In vitro generated Th1 and Th2 cells from myelin basic protein (MBP)-specific TCR transgenic mice were transferred into normal and immunodeficient mice. Th1 cells caused EAE in all recipients after a brief preclinical phase. Surprisingly, Th2 cells also caused EAE in RAG-1 KO mice and in αβ T cell–deficient mice, albeit after a longer preclinical phase. Normal or γδ T cell–deficient mice were resistant to EAE induced by Th2 cells. The histopathological features of this disease resembled those of an allergic process. In addition, disease induction by Th1 cells was not altered by coadmininstration of Th2 cells in any of the recipients. These findings indicate that MBP-specific Th2 cells have the potential to induce EAE and that the disease induced by previously activated Th1 cells cannot be prevented by normal lymphocytes nor by previously activated Th2 cells.
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Ohta, Nobuo, Shigeru Fukase, Takeo Fuse, and Masaru Aoyagi. "Th1 Th2, Tc1 Tc2 cells of patients with otolaryngological diseases." Allergology International 53, no. 3 (2004): 199–203. http://dx.doi.org/10.1111/j.1440-1592.2004.00335.x.
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Adkins, Becky, Yurong Bu, Vladimir Vincek, and Patricia Guevara. "The Primary Responses of Murine Neonatal Lymph Node CD4+Cells are Th2-skewed and are Sufficient for the Development of Th2-biased Memory." Clinical and Developmental Immunology 10, no. 1 (2003): 43–51. http://dx.doi.org/10.1080/10446670310001598474.
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Exposure of neonatal mice to antigen often results in Th2-biased responses in later life. Examples of this Th2 tendency are (a) secondary antibody responses dominated by the Th2-associated IgG1 isotype and (b) Th2-mediated tolerance to alloantigens. We previously reported that neonates develop primary Th1 and Th2 function in the lymph nodes but exclusive Th2 primary splenic responses. Here, we have tested whether the Th2 bias of adults initially immunized as neonates is due to the early, primary Th2 polarization in the spleen. Surprisingly, removal of the spleen at birth had no affect on either IgG1-dominant secondary responses or the development of tolerance to alloantigens. Thus, neonatal lymph nodes are sufficient to generate Th2-biased function following neonatal antigen exposure. To understand how this could arise, we examined the primary Th1/Th2 responses of CD4+lymph node cells. Unlike the balanced Th1/Th2 responses seen with total lymph node cells, the primary responses of isolated CD4+cells were skewed to IL-4 producing function. These results suggest that the early development of Th2-dominant responses by lymph node CD4+cells contributes substantially to the subsequent development of Th2-dominant memory in neonates.
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Nishimura, Takashi, Kenji Iwakabe, Masashi Sekimoto, Yasushi Ohmi, Takashi Yahata, Minoru Nakui, Takehito Sato, et al. "Distinct Role of Antigen-Specific T Helper Type 1 (Th1) and Th2 Cells in Tumor Eradication in Vivo." Journal of Experimental Medicine 190, no. 5 (September 6, 1999): 617–28. http://dx.doi.org/10.1084/jem.190.5.617.
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The role of T helper type 1 (Th1) and Th2 cells in tumor immunity was investigated using Th cells induced from ovalbumin (OVA)-specific T cell receptor transgenic mice. Although Th1 cells exhibited stronger cytotoxicity than Th2 cells, both cell types completely eradicated tumors when transferred into mice bearing A20 tumor cells transfected with the OVA gene (A20-OVA). Th1 cells eradicated the tumor mass by inducing cellular immunity, whereas Th2 cells destroyed the tumor by inducing tumor necrosis. Both Th1 and Th2 cells required CD8+ T cells to eliminate tumors, and neither of these cells were able to completely eliminate A20-OVA tumors from T and B cell–deficient RAG2−/− mice. Mice cured from tumors by Th1 and Th2 cell therapy rejected A20-OVA upon rechallenge, but CD8+ cytotoxic T lymphocytes were induced only from spleen cells prepared from cured mice by Th1 cell therapy. Moreover, we demonstrated that Th1 and Th2 cells used distinct adhesion mechanisms during tumor eradication: the leukocyte function-associated antigen (LFA)-1–dependent cell–cell adhesion step was essential for Th1 cell therapy, but not for Th2 cell therapy. These findings demonstrated for the first time the distinct role of antigen-specific Th1 and Th2 cells during eradication of established tumors in vivo.
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Besser, Michal, and Rudolf Wank. "Cutting Edge: Clonally Restricted Production of the Neurotrophins Brain-Derived Neurotrophic Factor and Neurotrophin-3 mRNA by Human Immune Cells and Th1/Th2-Polarized Expression of Their Receptors." Journal of Immunology 162, no. 11 (June 1, 1999): 6303–6. http://dx.doi.org/10.4049/jimmunol.162.11.6303.
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Abstract Neurotrophins, such as neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF), are potent regulators of neuronal functions. Here we show that human immune cells also produce NT-3 mRNA, secrete BDNF, and express their specific receptors trkB and trkC. The truncated trkB receptor, usually expressed in sensory neurons of the central nervous system, was also constitutively expressed in unstimulated Th cells. Full-length trkB was detectable in stimulated PBMC, B cell lines, and Th1, but not in Th2 and Th0 cell clones. Clonally restricted expression was also observed for trkC, until now not detected on blood cells. The Th1 cytokine IL-2 stimulated production of trkB mRNA but not of trkC, whereas the Th2 cytokine IL-4 enhanced NT-3 but not BDNF mRNA expression. Microbial Ags, which influence the Th1/Th2 balance, could therefore modulate the neurotrophic system and thereby affect neuronal synaptic activity of the central nervous system.
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Mariotti, Jacopo, Jason Foley, Kaitlyn Ryan, Nicole Buxhoeveden, Veena Kapoor, Shoba Amarnath, and Daniel H. Fowler. "Graft rejection as a Th1-type process amenable to regulation by donor Th2-type cells through an interleukin-4/STAT6 pathway." Blood 112, no. 12 (December 1, 2008): 4765–75. http://dx.doi.org/10.1182/blood-2008-05-154278.
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Abstract Graft rejection has been defined as the mirror image of graft-versus-host disease, which is biologically characterized primarily as a Th1-type process. As such, we reasoned that graft rejection would represent a Th1 response amenable to Th2 modulation. Indeed, adoptive transfer of host Th1-type cells mediated rejection of fully MHC-disparate murine bone marrow allografts more effectively than host Th2-type cells. Furthermore, STAT1-deficient host T cells did not differentiate into Th1-type cells in vivo and failed to mediate rejection. We next hypothesized that donor Th2 cell allograft augmentation would prevent rejection by modulation of the host Th1/Th2 balance. In the setting of donor Th2 cell therapy, host–anti-donor allospecific T cells acquired Th2 polarity, persisted posttransplantation, and did not mediate rejection. Abrogation of rejection required donor Th2 cell IL-4 secretion and host T-cell STAT6 signaling. In conclusion, T cell–mediated marrow graft rejection primarily resembles a Th1-type process that can be abrogated by donor Th2 cell therapy that promotes engraftment through a novel mechanism whereby cytokine polarization is transferred to host T cells.
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He, Guangsheng, Xiuli Wang, De Pei Wu, Aining Sun, and Zhengming Jin. "Subsets and Function Changes of Th Cells in the Bone Marrow of Patients with Immune Related Pancytopenia." Blood 106, no. 11 (November 16, 2005): 3762. http://dx.doi.org/10.1182/blood.v106.11.3762.3762.
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Abstract Objectives To explore the subsets and function of T helper (Th) in bone marrow of the patients with immune related pancytopenia(IRP). Methods The CD4+ cells producing IFN-γ or IL-4 in cytoplasm were defined as Th1 or Th2 cells respectively. All these cells in bone marrow were measured from 16 normal controls, 25 untreated IRP patients; The mRNA expressions of IL-4, IL-10, IFN-γ and IL-2 genes in unstimulated bone marrow mononuclear cells(BMMNC)from 25 untreated IRP patients, 10 normal controls were measured by reverse transcription polymerase chain reaction (RT-PCR). Results The percentage of Th1 cells, Th2 cells and ratio of Th1/Th2 in bone marrow of normal controls was: 0.42%, 0.24%, 1.57 respectively, and the percentage of Th1 cells in untreated patients with IRP was 0.58%, which was not markedly different from the that of normal controls(t=0.903, P>0.05). But the percentage of Th2 cells of the patients with IRP was significantly higher than that of normal controls(t=4.673, P<0.01), and the balance of Th1/Th2 shifted to Th2 more significantly by comparing to that of normal controls (t=4.880, P<0.01). The mRNA expressions of IL-4 and IL-10 in the Th2 cells of the untreated IRP patients were significantly higher than those of the normal controls, however difference of the expressions of IFN-γ and IL-2 in the Th1 cells were not significantly. Conclusions The percentage of Th2 cells increased in the patients with IRP, and the balance of Th1/Th2 shifted to Th2. And the expression of Th2 type cytokines was more frequent in IRP. The imbalance of subtypes of Th lymphocytes and hyperfunction of Th2 lymphocytes might play important roles in the pathogenic mechanism of IRP, which lead to more B lymphocytes and producing autoantibodies consistenly.
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Hawkins, Raymond A., Roger G. Rank, and Kathleen A. Kelly. "A Chlamydia trachomatis-Specific Th2 Clone Does Not Provide Protection against a Genital Infection and Displays Reduced Trafficking to the Infected Genital Mucosa." Infection and Immunity 70, no. 9 (September 2002): 5132–39. http://dx.doi.org/10.1128/iai.70.9.5132-5139.2002.
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ABSTRACT A T helper type 1 (Th1) response is essential for resolving genital infections with the mouse pneumonitis biovar of Chlamydia trachomatis (MoPn). However, T-cell-dependent anti-chlamydial antibody is produced and may also contribute to protective immunity. We produced a MoPn-specific CD4 Th2 clone (Th2-MoPn) to study the role of a Th2 response during infection. We found that Th2-MoPn was unable to eradicate chlamydiae from the genital tract (GT) when it was transferred into MoPn-infected nude mice. Mice that received Th2-MoPn produced greater titers of MoPn-specific serum immunoglobulin G (IgG) antibody than mice that received a MoPn-specific Th1 clone (Th1-MoPn) (log10 titers, 1.89 ± 0.84 and 0.58 ± 0.76 [mean ± standard deviation], respectively [P < 0.01]). Also, the IgG isotypes were different for the two groups; whereas IgG1 was associated with Th2-MoPn, IgG2a was associated with Th1-MoPn. Also, infected nude mice that received Th2-MoPn produced higher levels of IgA in vaginal secretions. Although clone Th2-MoPn was detected in the GT, it was less efficient at migrating (112 ± 35.6 labeled Th2 clone cells/105 GT cells) than Th1-MoPn (505 ± 51.6 Th1 clone cells/105 GT cells) (P < 0.001, as determined by a t test). This may have been due to reduced expression of α4β7 and P-selectin ligand 1 on Th2-MoPn. However, Th2-MoPn cells were retained in the GT during chronic infection and comprised 10 to 15% of the total GT cells 80 days after transfer. The data show that the MoPn-specific Th2 cells are important for serum and vaginal antibody production and may accumulate in the GT during chronic infection.
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Del Prete, G., M. De Carli, F. Almerigogna, M. G. Giudizi, R. Biagiotti, and S. Romagnani. "Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production." Journal of Immunology 150, no. 2 (January 15, 1993): 353–60. http://dx.doi.org/10.4049/jimmunol.150.2.353.
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Abstract IL-10 gene transcription and IL-10 protein production was assessed in both type 1 (Th1) and type 2 (Th2) CD4+ human T cell clones by polymerase chain reaction and ELISA, respectively. Although Th2 clones apparently showed higher IL-10 mRNA levels, IL-10 mRNA expression was consistently found in Th1 clones, as well. Likewise, measurable IL-10 levels were found in the supernatants of both Th1 and Th2 clones. The effect of human IL-10 (h-IL-10) and viral IL-10 (v-IL-10) on the proliferative response and cytokine production by Th1 and Th2 human clones was also investigated. Addition in culture of h-IL-10 and v-IL-10 significantly reduced the proliferation of both Th1 and Th2 clones in response to the specific Ag and to PHA, but it had no inhibitory effect on the proliferative response of Th1 and Th2 clones to IL-2. h-IL-10 and v-IL-10 also inhibited the Ag-induced production of gamma-interferon (IFN-gamma) by Th1 clones and the production of IL-4 and IL-5 by Th2 clones, whereas they had no effect on the cytokine synthesis by the same clones stimulated with PMA plus anti-CD3 antibody. Preincubation of APC, but not of clonal T blasts, with h-IL-10 resulted in the inhibition of Ag-induced proliferation of both Th1 and Th2 clones, supporting the view that h-IL-10 primarily affects APC. These data demonstrate that, unlike the murine system where IL-10 is a product of Th2 (but not Th1) cells and seems to mainly down-regulate the Th1 response, in the human system, IL-10 is produced by, and down-regulates the function of, both Th1 and Th2 cells.