Статті в журналах: "Th2-dependent"

1

Müller, K. M., F. Jaunin, I. Masouyé, J. H. Saurat, and C. Hauser. "Th2 cells mediate IL-4-dependent local tissue inflammation." Journal of Immunology 150, no. 12 (June 15, 1993): 5576–84. http://dx.doi.org/10.4049/jimmunol.150.12.5576.

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Abstract We investigated whether polyclonal murine Th1 and Th2 cells obtained after short term culture in vitro were capable of mediating tissue inflammation in vivo. Th cells were pulsed with mAb to the TCR/CD3 complex and injected into the footpads or ears of naive syngeneic recipient mice. Th1 induced delayed swelling that peaked at 24 to 48 h and lasted > or = 5 days. Th2-induced swelling peaked at 6 h and lasted < or = 48 h. Similar responses were also observed in athymic nude mice. Lesions with both Th1 and Th2 cells contained a predominant neutrophilic infiltrate at 6 h, and mainly mononuclear cells at 48 h. The inflammatory response with Th2 was blocked by cyclosporin A, by mAb to IL-4 or by soluble rIL-4R. The requirement for IL-4 was early and transient. Four alloreactive short term Th2 clones induced swelling in allogeneic recipients. mAb- and IL-4-dependent swelling responses were also observed with two long term Th2 clones. Our results demonstrate that Th2 cells mediate IL-4-dependent tissue inflammation, and strengthen the concept that Th2 cells play an important role in some T cell-dependent immune reactions and, possibly, in allergic disorders such as atopic dermatitis and allergic asthma.

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2

Foucras, Gilles, Christiane Coureau, Leo Beijleveld, Philippe Druet, Abdelhadi Saoudi та Jean-Charles Guéry. "β2-Microglobulin-Dependent T Cells Are Not Necessary for Alloantigen-Induced Th2 Responses After Neonatal Induction of Lymphoid Chimerism in Mice". Journal of Immunology 161, № 4 (15 серпня 1998): 1751–57. http://dx.doi.org/10.4049/jimmunol.161.4.1751.

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Abstract We have analyzed the requirement for β2-microglobulin (β2m)-dependent T cells in the generation of allogeneic Th2 responses in vivo. A neonatal injection of semiallogeneic cells in BALB/c mice induces a state of chimerism that promotes the differentiation of donor-specific CD4+ T cells toward the Th2 phenotype. Polyclonal T-B cell interactions occur in this model between host Th2 and donor B cells, resulting in the production of IgE Abs. IgE production and Th2-priming are critically dependent upon the early production of IL-4. Our data in the present paper demonstrate that: 1) IgE synthesis and the up-regulation of MHC class II and CD23 molecules on B cells are independent of β2m expression in the host, 2) no difference in the induction of CD4 alloreactive Th2 cells could be observed between β2m−/− and their wild-type control littermates when Th2-priming was measured in adult mice, and 3) the Th2 response and IgE production is induced in the complete absence of β2m-dependent T cells both in the host and in the inoculum. Therefore, using a variety of assays, we could not demonstrate diminished responses in mice with a disrupted β2m gene in this model of Th2-mediated allogeneic interaction, indicating that β2m-dependent NK1.1+ and CD8+ T cells are not required for the generation of alloreactive Th2 responses in vivo.

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3

Hasegawa, Akihiro, and Toshinori Nakayama. "Impaired GATA3-dependent chromatin remodeling and Th2 cell differentiation leading to attenuated allergic airway inflammation in aging mice (85.1)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S118. http://dx.doi.org/10.4049/jimmunol.178.supp.85.1.

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Abstract Age-related changes in lymphocytes are most prominent in the T cell compartment. In the present study, we used 8–12 month-old aging mice and a well-established in vitro Th1/Th2 cell differentiation culture system to identify molecular defects in Th1/Th2 cell differentiation that can be detected in the relatively early stages of aging. The capability to differentiate into Th2 cells is reduced in aging mouse CD4+ T cells. Decreased activation of the ERK MAPK cascade upon TCR stimulation, but normal [Ca2+]i mobilization and normal IL-4-induced STAT6 activation were observed in aging mouse CD4+ T cells. In addition, reduced expression of GATA3 was detected in developing Th2 cells. Chromatin remodeling of the Th2 cytokine gene locus was found to be impaired. Th2-dependent allergic airway inflammation was milder in aging mice compared with in young adult mice. These results suggest that the levels of Th2 cell differentiation and resulting Th2-dependent immune responses, including allergic airway inflammation, decline during aging through defects in the activation of the ERK MAPK cascade, expression of GATA3 protein and GATA3-dependent chromatin remodeling of the Th2 cytokine gene locus. In the present study, we provide the first evidence indicating that a chromatin-remodeling event in T cells is impaired by aging.

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4

Tjota, Melissa, Kelly Blaine, Nora Barrett та Anne Sperling. "Signaling through FcRγ receptors on dendritic cells drives IL-33 dependent Th2-type responses (HYP6P.262)". Journal of Immunology 192, № 1_Supplement (1 травня 2014): 118.7. http://dx.doi.org/10.4049/jimmunol.192.supp.118.7.

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Abstract Dendritic cells (DCs) play a critical role in the development of Th2 responses during atopic asthma, but the mechanism by which allergens drive DCs to promote Th2 responses is still unclear. Previously, we demonstrated that allergen-specific IgG immune complexes (ICs) enhance secondary Th2 responses via an IL-33-dependent mechanism by ligating FcγRIII on antigen presenting cells. To identify if this pathway was common to other Th2 stimuli, we used house dust mite (HDM) extract. While HDM-mediated allergic inflammation was not dependent on FcγRIII, it was reliant on the common signaling component FcRγ as FcRγ-/- mice failed to develop Th2 responses in the lung. Notably, ligation of FcRγ associated receptors, FcγRIII and Dectin-2, on DCs treated with ICs or HDM respectively, upregulated IL-33 in an FcRγ and PI3-kinase dependent manner suggesting a common pathway by which Th2 stimuli can direct the development of DCs that induce Th2 differentiation. Reestablishment of Th2 responses in the FcRγ-/- mice with an adoptive transfer of HDM-sensitized FcRγ+/- DCs indicated that the lack of response in the FcRγ-/- mice was due to a deficient response from the DCs. Interestingly, addition of recombinant IL-33 during HDM sensitization was sufficient to restore airway inflammation in FcRγ-/- mice. Overall, these data identify a mechanism whereby Th2 stimuli signal through FcRγ associated receptors on DCs to upregulate IL-33 production and induce Th2-mediated allergic airway inflammation.

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5

Zhou, Meixia, Wenjun Ouyang, Qian Gong, Samuel G. Katz, J. Michael White, Stuart H. Orkin, and Kenneth M. Murphy. "Friend of GATA-1 Represses GATA-3–dependent Activity in CD4+ T Cells." Journal of Experimental Medicine 194, no. 10 (November 12, 2001): 1461–71. http://dx.doi.org/10.1084/jem.194.10.1461.

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The development of naive CD4+ T cells into a T helper (Th) 2 subset capable of producing interleukin (IL)-4, IL-5, and IL-13 involves a signal transducer and activator of transcription (Stat)6-dependent induction of GATA-3 expression, followed by Stat6-independent GATA-3 autoactivation. The friend of GATA (FOG)-1 protein regulates GATA transcription factor activity in several stages of hematopoietic development including erythrocyte and megakaryocyte differentiation, but whether FOG-1 regulates GATA-3 in T cells is uncertain. We show that FOG-1 can repress GATA-3–dependent activation of the IL-5 promoter in T cells. Also, FOG-1 overexpression during primary activation of naive T cells inhibited Th2 development in CD4+ T cells. FOG-1 fully repressed GATA-3–dependent Th2 development and GATA-3 autoactivation, but not Stat6-dependent induction of GATA-3. FOG-1 overexpression repressed development of Th2 cells from naive T cells, but did not reverse the phenotype of fully committed Th2 cells. Thus, FOG-1 may be one factor capable of regulating the Th2 development.

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6

Ho, I.-Cheng, David Lo, and Laurie H. Glimcher. "c-maf Promotes T Helper Cell Type 2 (Th2) and Attenuates Th1 Differentiation by Both Interleukin 4–dependent and –independent Mechanisms." Journal of Experimental Medicine 188, no. 10 (November 16, 1998): 1859–66. http://dx.doi.org/10.1084/jem.188.10.1859.

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The c-maf protooncogene is a T helper cell type 2 (Th2)-specific transcription factor that activates the interleukin (IL)-4 promoter in vitro. Although it has been postulated that c-maf directs the Th2-specific expression of the IL-4 gene in vivo, direct evidence that c-maf functions during the differentiation of normal, primary T cells is lacking. We now demonstrate that overexpression of c-maf in vivo skews the Th immune response along a Th2 pathway, as evidenced by increased production of Th2 cytokines and the IL-4–dependent immunoglobulins, IgG1 and IgE. The overproduction of IgGl and IgE in the CD4 promoter/c-maf transgenic mice was IL-4 dependent since this was not observed in c-maf transgenic mice bred onto an IL-4–deficient background. Ectopic expression of c-maf in mature Th1 cells did not confer on them the ability to produce IL-4, but did decrease the production of IFN-γ. The attenuation of Th1 differentiation by c-maf overexpression occurred by a mechanism that was independent of IL-4 and other Th2 cytokines, and could be overcome by IL-12. These studies demonstrate that c-maf promotes Th2 differentiation by IL-4–dependent mechanisms and attenuates Th1 differentiation by Th2 cytokine-independent mechanisms.

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7

Kaplan, Mark H., Andrea L. Wurster, Stephen T. Smiley, and Michael J. Grusby3. "Stat6-Dependent and -Independent Pathways for IL-4 Production." Journal of Immunology 163, no. 12 (December 15, 1999): 6536–40. http://dx.doi.org/10.4049/jimmunol.163.12.6536.

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Abstract Stat6 has been shown to have a crucial role in the IL-4-dependent differentiation of Th2 cells. In this report, we explore whether in vitro Th2 differentiation driven by altered costimulatory signals or Ag dose is Stat6 dependent. We find that blocking B7-1 signaling in vitro promotes the differentiation of IL-4-secreting Th2 cells in wild-type but not Stat6-deficient T cell cultures. Additionally, stimulation with peptide Ag doses that normally result in the production of Th2 cells in vitro fails to do so in cultures of Stat6-deficient cells. We also demonstrate that Stat6 is required for the in vitro differentiation of CD8+ T cells into IL-4-secreting cytotoxic T cell type 2 cells. However, IL-4 expression is not absolutely dependent on Stat6. We demonstrate that populations of T cells that do not require IL-4 for their development, such as NK T cells, are still competent to secrete IL-4 in the absence of Stat6. These results demonstrate that Stat6 is required for the differentiation program leading to the generation of Th2 and cytotoxic T cell type 2 cells but not for IL-4 expression in cells that do not undergo differentiation in response to IL-4.

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8

Magalhaes, Joao Gamelas, Jörg H. Fritz, Lionel Le Bourhis, Gernot Sellge, Leonardo H. Travassos, Thirumahal Selvanantham, Stephen E. Girardin, Jennifer L. Gommerman, and Dana J. Philpott. "Nod2-Dependent Th2 Polarization of Antigen-Specific Immunity." Journal of Immunology 181, no. 11 (November 18, 2008): 7925–35. http://dx.doi.org/10.4049/jimmunol.181.11.7925.

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9

Kim, Daniel C., F. Ida Hsu, Nora A. Barrett, Daniel S. Friend, Roland Grenningloh, I.-Cheng Ho, Amal Al-Garawi, et al. "Cysteinyl Leukotrienes Regulate Th2 Cell-Dependent Pulmonary Inflammation." Journal of Immunology 176, no. 7 (March 17, 2006): 4440–48. http://dx.doi.org/10.4049/jimmunol.176.7.4440.

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10

Hook, Sarah, Melanie Prout, Mali Camberis, Monika Konig, Andreas Zimmer, Gino Van Heeke, and Graham Le Gros. "Th2-dependent airway eosinophilia is regulated by preproenkephalin." Journal of Neuroimmunology 107, no. 1 (July 2000): 59–65. http://dx.doi.org/10.1016/s0165-5728(00)00243-5.

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11

Sharma, Hemant P., and Elizabeth C. Matsui. "Cysteinyl Leukotrienes Regulate Th2 Cell-Dependent Pulmonary Inflammation." Pediatrics 120, Supplement 3 (November 2007): S131—S132. http://dx.doi.org/10.1542/peds.2007-0846zz.

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12

Maier, Elisabeth, Albert Duschl, and Jutta Horejs-Hoeck. "STAT6-dependent and -independent mechanisms in Th2 polarization." European Journal of Immunology 42, no. 11 (October 8, 2012): 2827–33. http://dx.doi.org/10.1002/eji.201242433.

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13

Minoprio, P. "Chagas' disease: CD5 B-cell-dependent Th2 pathology?" Research in Immunology 142, no. 2 (January 1991): 137–40. http://dx.doi.org/10.1016/0923-2494(91)90024-d.

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14

Lee, Seung-Hyo, Farrah Kheradmand, and David Corry. "Developmental Control of Integrin Expression Regulates T Helper-2 Effector Homing (99.6)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S195. http://dx.doi.org/10.4049/jimmunol.178.supp.99.6.

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Abstract Integrin CD18, a component of the lymphocyte function-associated antigen-1 (LFA-1) complex that also includes CD11a, is essential for Th2, but not Th1, cell homing, but the explanation for this phenomenon remains obscure. Here, we investigate the mechanism by which Th2 effector responses require the LFA-1 complex. CD11a-deficient T cells showed normal in vitro differentiation and function. However, Th2 cell-dependent allergic lung disease was markedly reduced in CD11a null mice and wild type mice given LFA-1 inhibitors, whereas control of infection with Leishmania major, a Th1-dependent response, was enhanced. In both disease models, recruitment of IL-4−, but not IFN-g, secreting cells to relevant organs was impaired, as was adhesion of Th2 cells in vitro. These diverse findings were explained by the markedly reduced expression of CD29, an alternate homing integrin, on Th2, but not Th1, cells, which precludes Th2 homing in the absence of CD11a. Thus, murine Th1 and Th2 cells utilize distinct integrins for homing, suggesting novel opportunities for integrin-based therapeutic intervention in diverse human ailments.

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15

Altin, John, Chris Goodnow, and Matthew Cook. "IL-10 production by Th2 cells in vivo occurs by sub-differentiation into a novel, suppressive IL-10+CTLA-4hi Th2 subset (152.28)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 152.28. http://dx.doi.org/10.4049/jimmunol.186.supp.152.28.

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Abstract IL-10 is a critical regulatory cytokine that can be produced by many cell-types of the immune system, including IL-4-producing Th2 cells where it was first identified. However, current knowledge of Th2 cell IL-10 production comes largely from cultures in vitro, and little is known about how IL-10 is regulated at the single cell level during Th2 cell differentiation in vivo. Here, by directly measuring and manipulating IL-4 and/or IL-10-producing cells formed during inflammatory responses in vivo, we show that Th2 cells acquire the ability to produce IL-10 as part of a regulated differentiation process. This process is characterised by the co-ordinate upregulation of a program of other ‘regulatory’ genes, particularly CTLA-4. Differentiation is exquisitely dependent on Card11-dependent external signals that condition IL-10-CTLA-4lo ‘early’ Th2 cells to become IL-2-responsive IL-10-CTLA-4int Th2 ‘intermediates’. Upon exposure to cytokines such as IL-2, IL-10 and IL-21, these intermediates progress into IL-10+CTLA-4hi ‘end state’ Th2 cells that have potent suppressive function. Our findings define a novel process of external signal-regulated Th2 cell sub-differentiation in vivo, culminating in a suppressive subset that may account for negative feedback during chronic Th2 responses.

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16

Tanaka, Hiroyuki, Christian E. Demeure, Manuel Rubio, Guy Delespesse, and Marika Sarfati. "Human Monocyte–Derived Dendritic Cells Induce Naive T Cell Differentiation into T Helper Cell Type 2 (Th2) or Th1/Th2 Effectors." Journal of Experimental Medicine 192, no. 3 (August 7, 2000): 405–12. http://dx.doi.org/10.1084/jem.192.3.405.

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The subset of dendritic cells (DCs) and the nature of the signal inducing DC maturation determine the capacity of DCs to generate polarized immune responses. In this study, we show that the ability of human monocyte-derived DCs (myeloid DC1) to promote T helper type 1 (Th1) or Th2 differentiation was also found to be critically dependent on stimulator/responder ratio. At a low ratio (1:300), mature DCs that have been differentiated after inflammatory (Staphylococcus aureus Cowan 1 or lipopolysaccharide) or T cell–dependent (CD40 ligand) stimulation induced naive T cells to become Th2 (interleukin [IL]-4+, IL-5+, interferon γ) effectors. Th2 differentiation was dependent on B7–CD28 costimulation and enhanced by OX40–OX40 ligand interactions. However, high DC/T cell ratio (1:4) favored a mixed Th1/Th2 cell development. Thus, the fact that the same DC lineage stimulates polarized Th1 or Th2 responses may be relevant since it allows the antigen-presenting cells to initiate an appropriate response for the signal received at the peripheral sites. Controlling the number and the rate of DC migration to the T cell areas in lymphoid tissues may be important for the therapeutic use of DCs.

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17

Hessel, Edith M., Mabel Chu, Jennifer O. Lizcano, Bonnie Chang, Nancy Herman, Sariah A. Kell, Marsha Wills-Karp, and Robert L. Coffman. "Immunostimulatory oligonucleotides block allergic airway inflammation by inhibiting Th2 cell activation and IgE-mediated cytokine induction." Journal of Experimental Medicine 202, no. 11 (November 28, 2005): 1563–73. http://dx.doi.org/10.1084/jem.20050631.

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A single treatment with a CpG-containing immunostimulatory DNA sequence (ISS) given before allergen challenge can inhibit T helper type 2 cell (Th2)–mediated airway responses in animal models of allergic asthma; however, the mechanism of this inhibition remains largely undefined. Here, we demonstrate that airway delivery of ISS before allergen challenge in Th2-primed mice acts in two distinct ways to prevent the allergic responses to this challenge. The first is to prevent induction of cytokines from allergen-specific Th2 cells, as demonstrated by the nearly complete inhibition of Th2 cytokine production, Th2-dependent functional responses, and gene induction patterns. ISS inhibits the Th2 response by rendering lung antigen-presenting cells (APCs) unable to effectively present antigen to Th2 cells, but not to Th1 cells. This loss of APC function correlates with a reduced expression of costimulatory molecules, including programmed cell death ligand (PD-L)1, PD-L2, CD40, CD80, CD86, and inducible T cell costimulator, and of major histocompatibility complex class II on CD11c+APCs from the airways of ISS-treated mice. The second important action of ISS is inhibition of immunoglobulin E–dependent release of Th2 cytokines, especially interleukin 4, from basophils and/or mast cells in the airways of Th2-primed mice. Thus, inhibition by ISS of allergic responses can be explained by two novel mechanisms that culminate in the inhibition of the principal sources of type 2 cytokines in the airways.

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18

Pivniouk, Vadim, Tom Bailey, Oksana Pivniouk, Patricia Kiesler, Gabriela Wlasiuk, David Rosenbaum, Kenneth Kim, Jannine Strempel, Michael Daines, and Donata Vercelli. "Faithful epigenetic and transcriptional regulation of a transgenic human Th2 cytokine gene locus in the murine nuclear environment (51.1)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 51.1. http://dx.doi.org/10.4049/jimmunol.184.supp.51.1.

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Abstract Dysregulated production of the Th2 cytokines IL4 and IL13 is a hallmark of allergy and asthma. Th2 cytokine gene locus regulation has been extensively studied in mice, much less in humans. We have generated mice carrying a 160 kb BAC transgene (BAC5) that encompasses human RAD50, IL13 and IL4 and includes all the elements known to be required for faithful regulation of mouse Th2 cytokine locus. BAC5 transgenic mice appeared normal, were born at the expected Mendelian ratio, and carried 1-15 intact copies of BAC5. In vitro polarized mouse transgenic CD4 Th2, but not Th1 cells expressed human IL13 and IL4, demonstrating tissue-specific regulation of human Th2 cytokines. Murine CD4 T cells expressed physiologic levels of human IL13 and IL4, particularly in a house dust mite immunization model. Human IL13 expression was transgene copy number-dependent, suggesting BAC5 includes the human Th2 locus control region. Notably, DNA methylation patterns at multiple DNase I hypersensitive sites in the Th2 locus of human CD4 T cells were highly comparable if not identical in transgenic CD4 T cells of equivalent differentiation stages. Our results support the notion that in homologous tissues, genetic sequence is largely responsible for directing transcriptional programs and chromatin modifications even in a heterologous nuclear environment. Moreover, our findings suggest BAC5 transgenic mice are a powerful tool to study human Th2 cytokine gene regulation and Th2-dependent events in vivo.

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19

Yamashita, Masakatsu, Makoto Kuwahara, Akane Suzuki, Kiyoshi Hirahara, Ryo Shinnaksu, Hiroyuki Hosokawa, Akihiro Hasegawa, Shinichiro Motohashi, Atsushi Iwama, and Toshinori Nakayama. "Bmi1 regulates memory CD4 T cell survival via repression of the Noxa gene." Journal of Experimental Medicine 205, no. 5 (April 14, 2008): 1109–20. http://dx.doi.org/10.1084/jem.20072000.

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The maintenance of memory T cells is central to the establishment of immunological memory, although molecular details of the process are poorly understood. In the absence of the polycomb group (PcG) gene Bmi1, the number of memory CD4+ T helper (Th)1/Th2 cells was reduced significantly. Enhanced cell death of Bmi1−/− memory Th2 cells was observed both in vivo and in vitro. Among various proapoptotic genes that are regulated by Bmi1, the expression of proapoptotic BH3-only protein Noxa was increased in Bmi1−/− effector Th1/Th2 cells. The generation of memory Th2 cells was restored by the deletion of Noxa, but not by Ink4a and Arf. Direct binding of Bmi1 to the Noxa gene locus was accompanied by histone H3-K27 methylation. The recruitment of other PcG gene products and Dnmt1 to the Noxa gene was highly dependent on the expression of Bmi1. In addition, Bmi1 was required for DNA CpG methylation of the Noxa gene. Moreover, memory Th2-dependent airway inflammation was attenuated substantially in the absence of Bmi1. Thus, Bmi1 controls memory CD4+ Th1/Th2 cell survival and function through the direct repression of the Noxa gene.

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20

Skapenko, Alla, Jan Leipe, Uwe Niesner, Koen Devriendt, Rolf Beetz, Andreas Radbruch, Joachim R. Kalden, Peter E. Lipsky, and Hendrik Schulze-Koops. "GATA-3 in Human T Cell Helper Type 2 Development." Journal of Experimental Medicine 199, no. 3 (February 2, 2004): 423–28. http://dx.doi.org/10.1084/jem.20031323.

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The delineation of the in vivo role of GATA-3 in human T cell differentiation is a critical step in the understanding of molecular mechanisms directing human immune responses. We examined T cell differentiation and T cell–mediated effector functions in individuals lacking one functional GATA-3 allele. CD4 T cells from GATA-3+/− individuals expressed significantly reduced levels of GATA-3, associated with markedly decreased T helper cell (Th)2 frequencies in vivo and in vitro. Moreover, Th2 cell–mediated effector functions, as assessed by serum levels of Th2-dependent immunoglobulins (Igs; IgG4, IgE), were dramatically decreased, whereas the Th1-dependent IgG1 was elevated compared with GATA-3+/+ controls. Concordant with these data, silencing of GATA-3 in GATA-3+/+ CD4 T cells with small interfering RNA significantly reduced Th2 cell differentiation. Moreover, GATA-3 mRNA levels increased under Th2-inducing conditions and decreased under Th1-inducing conditions. Taken together, the data strongly suggest that GATA-3 is an important transcription factor in regulating human Th2 cell differentiation in vivo.

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21

De Monte, Lucia, Michele Reni, Elena Tassi, Daniela Clavenna, Ilenia Papa, Helios Recalde, Marco Braga, Valerio Di Carlo, Claudio Doglioni, and Maria Pia Protti. "Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer." Journal of Experimental Medicine 208, no. 3 (February 21, 2011): 469–78. http://dx.doi.org/10.1084/jem.20101876.

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Pancreatic cancer is a very aggressive disease characterized by a marked desmoplasia with a predominant Th2 (GATA-3+) over Th1 (T-bet+) lymphoid infiltrate. We found that the ratio of GATA-3+/T-bet+ tumor-infiltrating lymphoid cells is an independent predictive marker of patient survival. Patients surgically treated for stage IB/III disease with a ratio inferior to the median value had a statistically significant prolonged overall survival, implying an active role for Th2 responses in disease progression. Thymic stromal lymphopoietin (TSLP), which favors Th2 cell polarization through myeloid dendritic cell (DC) conditioning, was secreted by cancer-associated fibroblasts (CAFs) after activation with tumor-derived tumor necrosis factor α and interleukin 1β. TSLP-containing supernatants from activated CAFs induced in vitro myeloid DCs to up-regulate the TSLP receptor (TSLPR), secrete Th2-attracting chemokines, and acquire TSLP-dependent Th2-polarizing capability in vitro. In vivo, Th2 chemoattractants were expressed in the tumor and in the stroma, and TSLPR-expressing DCs were present in the tumor stroma and in tumor-draining but not in nondraining lymph nodes. Collectively, this study identifies in pancreatic cancer a cross talk between tumor cells and CAFs, resulting in a TSLP-dependent induction of Th2-type inflammation which associates with reduced patient survival. Thus, blocking TSLP production by CAFs might help to improve prognosis in pancreatic cancer.

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22

Hosokawa, Hiroyuki, Tomoaki Tanaka, Miki Kato, Yuuki Tamaki, and Toshinori Nakayama. "Functionally distinct Gata3/Chd4 complexes coordinately establish Th2 cell identity. (P1340)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 208.13. http://dx.doi.org/10.4049/jimmunol.190.supp.208.13.

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Abstract Gata3 is a GATA family transcription factor that controls differentiation of naïve CD4 T cells into T helper (Th) 2 cells. However, it is unknown how Gata3 simultaneously activates Th2-specific genes while repressing those of other Th lineages. Here we show that Chd4 (chromodomain helicase DNA-binding protein 4) forms a complex with Gata3 in Th2 cells that both activates Th2 cytokine transcription and represses the Th1 cytokine IFNγ. We define a Gata3/Chd4/p300 transcriptional activation complex at the Th2 cytokine loci and a Gata3/Chd4-NuRD repression complex at the Tbx21 locus in Th2 cells. We also demonstrated a physiological role for Chd4 in Th2-dependent inflammation in an in vivo model of asthmatic inflammation. Thus, Gata3/Chd4 forms functionally distinct complexes, which mediate both positive and negative gene regulation to facilitate Th2 cell differentiation.

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23

Aloisi, Francesca, Giuseppe Penna, Elisabetta Polazzi, Luisa Minghetti та Luciano Adorini. "CD40-CD154 Interaction and IFN-γ Are Required for IL-12 But Not Prostaglandin E2 Secretion by Microglia During Antigen Presentation to Th1 Cells". Journal of Immunology 162, № 3 (1 лютого 1999): 1384–91. http://dx.doi.org/10.4049/jimmunol.162.3.1384.

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Abstract IL-12 and PGE2 promote and inhibit, respectively, the development of Th1 responses. Production of these mediators by APC residing in the central nervous system (CNS) may be involved in the local regulation of the T cell phenotype during infectious and autoimmune CNS diseases. In the present study we have examined IL-12 and PGE2 secretion by cultured microglia and astrocytes from the mouse brain upon Ag-dependent interaction with I-Ad-restricted, OVA323–339 specific TCR transgenic Th1 and Th2 cell lines. We show that microglia, which restimulate efficiently both Th1 and Th2 cells, secrete IL-12 upon Ag-dependent interaction with Th1, but not with Th2 cells. Th1-driven IL-12 production depends on TCR ligation by MHC class II/peptide complexes, CD40 engagement on microglia, and IFN-γ secretion by activated Th1 cells. Th1 and, to a lesser extent, Th2 cells also stimulate the production of PGE2 by microglia. T cell-mediated induction of PGE2 requires MHC class II/peptide/TCR interactions but does not depend on CD40 engagement or on the presence of IFN-γ. Astrocytes, which preferentially activate Th2 cells, fail to produce IL-12 and secrete negligible amounts of PGE2 upon interaction with either Th1 or Th2 cells. These results suggest that during CNS infection or immunopathology, IL-12 produced by microglia upon Ag-specific interaction with Th1 cells may further skew the immune response to Th1, whereas the T cell-dependent production of PGE2 by microglia may represent a negative feedback mechanism, limiting the propagation of Th1 responses.

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Nair, Meera G., Yurong Du, Jacqueline G. Perrigoue, Colby Zaph, Justin J. Taylor, Michael Goldschmidt, Gary P. Swain та ін. "Alternatively activated macrophage-derived RELM-α is a negative regulator of type 2 inflammation in the lung". Journal of Experimental Medicine 206, № 4 (6 квітня 2009): 937–52. http://dx.doi.org/10.1084/jem.20082048.

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Differentiation and recruitment of alternatively activated macrophages (AAMacs) are hallmarks of several inflammatory conditions associated with infection, allergy, diabetes, and cancer. AAMacs are defined by the expression of Arginase 1, chitinase-like molecules, and resistin-like molecule (RELM) α/FIZZ1; however, the influence of these molecules on the development, progression, or resolution of inflammatory diseases is unknown. We describe the generation of RELM-α–deficient (Retnla−/−) mice and use a model of T helper type 2 (Th2) cytokine-dependent lung inflammation to identify an immunoregulatory role for RELM-α. After challenge with Schistosoma mansoni (Sm) eggs, Retnla−/− mice developed exacerbated lung inflammation compared with their wild-type counterparts, characterized by excessive pulmonary vascularization, increased size of egg-induced granulomas, and elevated fibrosis. Associated with increased disease severity, Sm egg–challenged Retnla−/− mice exhibited elevated expression of pathogen-specific CD4+ T cell–derived Th2 cytokines. Consistent with immunoregulatory properties, recombinant RELM-α could bind to macrophages and effector CD4+ Th2 cells and inhibited Th2 cytokine production in a Bruton's tyrosine kinase–dependent manner. Additionally, Retnla−/− AAMacs promoted exaggerated antigen-specific Th2 cell differentiation. Collectively, these data identify a previously unrecognized role for AAMac-derived RELM-α in limiting the pathogenesis of Th2 cytokine-mediated pulmonary inflammation, in part through the regulation of CD4+ T cell responses.

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Jang, Sung Woong, and Gap Ryol Lee. "GATA3, SATB1, IRF4 complex binds to the Th2 cytokine locus through cis-acting element RHS6, regulating allergic airway inflammation." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 44.35. http://dx.doi.org/10.4049/jimmunol.200.supp.44.35.

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Abstract Rad50 hypersensitive site 6 (RHS6) is a cis-acting element in the Th2 locus control region which is essential for the expression of Th2 cytokine genes. However, molecular mechanisms how it regulates the genes are poorly understood. We found that RHS6 recruits transcription factors GATA3, SATB1, and IRF4 during Th2 cell differentiation. GATA3, SATB1, and IRF4 have a crucial role in regulating Th2 cytokine genes. Knock-out or knock-down of each of GATA3, SATB1, and IRF4 genes significantly decrease the expression of Th2 cytokine genes. Mechanistically RHS6 mediates the transcription factor-induced regulation of Th2 cytokine genes. GATA3, SATB1, and IRF4 physically associates with each other, and forms a protein complex at RHS6 sequence. They directly bind to the many regulatory elements throughout the Th2 cytokine locus, RHS6 dependent manner. Furthermore, deletion of RHS6 caused a dramatic resistance to airway inflammation in ovalbumin-induced allergic inflammation model. Together, RHS6 recruits GATA3, SATB1, and IRF4 coordinating their regulation of Th2 cytokine genes, so is essential for Th2-mediated allergic airway inflammation.

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Cenci, Elio, Antonella Mencacci, Giuseppe Del Sero, Cristiana Fé d’Ostiani, Paolo Mosci, Angela Bacci, Claudia Montagnoli, Manfred Kopf та Luigina Romani. "IFN-γ Is Required for IL-12 Responsiveness in Mice with Candida albicans Infection". Journal of Immunology 161, № 7 (1 жовтня 1998): 3543–50. http://dx.doi.org/10.4049/jimmunol.161.7.3543.

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Abstract To elucidate the role of IFN-γ in antifungal CD4+ Th-dependent immunity, 129/Sv/Ev mice deficient for IFN-γ receptor (IFN-γR−/−) were assessed for susceptibility to gastrointestinal or systemic Candida albicans infection and for parameters of innate and adaptive T helper immunity. IFN-γR−/− mice failed to mount protective Th1-mediated acquired immunity upon mucosal immunization or in response to a live vaccine strain of the yeast. The impaired Th1-mediated resistance correlated with defective IL-12 responsiveness, but not IL-12 production, and occurred in the presence of an increased innate antifungal resistance. The development of nonprotective Th2 responses was observed in IFN-γR−/− mice upon mucosal infection and subsequent reinfection. However, under experimental conditions of Th2 cell activation, the occurrence of Th2 cell responses was similar in IFN-γR−/− and in IFN-γR+/+ mice. These results indicate the complex immunoregulatory role of IFN-γ in the induction of mucosal and nonmucosal anticandidal Th cell responses; IFN-γ is not essential for the occurrence of Th2 responses but is required for development of IL-12-dependent protective Th1-dependent immunity.

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Batra, Arvind, Besir Okur, Rainer Glauben, Ulrike Erben, Jakob Ihbe, Thorsten Stroh, Inka Fedke, Hyun-Dong Chang, Martin Zeitz, and Britta Siegmund. "Leptin: A Critical Regulator of CD4+ T-cell Polarization in Vitro and in Vivo." Endocrinology 151, no. 1 (January 1, 2010): 56–62. http://dx.doi.org/10.1210/en.2009-0565.

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Abstract Besides being mandatory in the metabolic system, adipokines like leptin directly affect immunity. Leptin was found to be necessary in T helper 1 (Th1)-dependent inflammatory processes, whereas effects on Th2 cells are rarely understood. Here, we focused on leptin in T-helper cell polarization and in Th2-mediated intestinal inflammation in vivo. The induction of cytokine-producing Th1 or Th2 cells from naive CD4+ T cells under polarizing conditions in vitro was generally decreased in cells from leptin-deficient ob/ob mice compared with wild-type mice. To explore the in vivo relevance of leptin in Th2-mediated inflammation, the model of oxazolone-induced colitis was employed in wild-type, ob/ob, and leptin-reconstituted ob/ob mice. Ob/ob mice were protected, whereas wild-type and leptin-reconstituted ob/ob mice developed colitis. The disease severity went in parallel with local production of the Th2 cytokine IL-13. A possible explanation for the protection of ob/ob mice in Th1- as well as in Th2-dependent inflammation is provided by a decreased expression of the key transcription factors for Th1 and Th2 polarization, T-bet and GATA-3, in naive ob/ob T cells. In conclusion, these results support the regulatory function of the adipokine leptin within T-cell polarization and thus in the acquired immune system and support the concept that there is a close interaction with the endocrine system.

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Gajewski, T. F., S. R. Schell, and F. W. Fitch. "Evidence implicating utilization of different T cell receptor-associated signaling pathways by TH1 and TH2 clones." Journal of Immunology 144, no. 11 (June 1, 1990): 4110–20. http://dx.doi.org/10.4049/jimmunol.144.11.4110.

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Abstract We have reported recently that high concentrations of anti-CD3 mAb inhibited IL-2-dependent proliferation of TH1 but not TH2 clones. The selective inhibitory effect on TH1 clones suggested that the two helper T lymphocyte subsets might utilize different TCR-associated signal transduction mechanisms. In the present study, we demonstrate that this distinction was not due to a gross difference in the level of TCR expression by TH1 and TH2 clones. Inhibition of TH1 proliferation by anti-CD3 mAb appeared to depend on calcium for maximal effect, suggesting that a substantial elevation of intracellular free calcium concentration ([Ca2+]i) might not occur after ligation of the TCR complex of TH2 clones. Calcium ionophore inhibited IL-2-dependent proliferation of both subsets, suggesting that receptor/ligand systems which stimulate elevated [Ca2+]i would be expected to inhibit proliferation. Although elevated [Ca2+]i and generation of inositol phosphates were readily detected in TH1 clones, these second messengers were not detected following stimulation of TH2 clones via the TCR complex. In addition, lymphokine production by TH1 clones was more sensitive to inhibition by cholera toxin, 8-bromoadenosine 3':5'-cyclic monophosphate, and cyclosporin A than was lymphokine production by TH2 clones. Collectively, these results suggest that TH1 and TH2 clones utilize distinct TCR-associated signal transduction mechanisms for lymphokine gene expression. The difference in signaling mechanisms suggests a potential pharmacologic target for intervention in situations where inappropriate activation of TH1 or TH2 cells occurs in vivo.

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Pivniouk, Vadim, Tom Bailey, Oksana Pivniouk, David Rosenbaum, Sara Mobley, Debra Stern, Marilyn Halonen, and Donata Vercelli. "Asthma-associated IL13 single nucleotide polymorphisms (SNPs) upregulate human IL4 expression in mice carrying a human Th2 locus BAC transgene (57.10)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 57.10. http://dx.doi.org/10.4049/jimmunol.188.supp.57.10.

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Abstract A block of 9 SNPs in human (h) IL13 is strongly associated with increased susceptibility to allergy and asthma in multiple human populations. To study the functional significance of these SNPs in vivo, we generated mice that carry a 160 kb BAC5 transgene (TG) encompassing a non-polymorphic hTh2 cytokine locus (HapI). A HapII TG was engineered by introducing the asthma-associated IL13 SNPs into BAC5. hTh2 cytokine expression was faithfully regulated in HapI and HapII mice. To evaluate the effects of asthma-associated SNPs, we compared Th2 cytokine expression by polarized Th2 cells from Hap I and Hap II mice. Mouse Th2 cytokine expression was unaffected. hIL13 secretion was marginally upregulated in Hap II mice but, surprisingly, hIL4 protein and mRNA levels were dramatically increased. Increased hIL4 expression in carriers of IL13 SNPs was confirmed in humans. To elucidate the mechanisms underlying the effects of hIL13 SNPs on hIL4 expression, we performed a high-resolution analysis of DNA methylation at the Th2 cytokine locus in HapI and HapII Th2 cells. Several differentially methylated regions were identified. Notably, the HSIV element that is located ~25 kb 3’ of the IL13 SNPs and acts as an IL4 silencer in mice, was significantly hypermethylated at three consecutive CpG sites in HapII Th2 cells. Collectively, our results point to novel long-range effects of the IL13 SNPs on HSIV-dependent IL4 silencing, which may increase susceptibility to Th2-dependent allergic disease.

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Tao, X., S. Constant, P. Jorritsma, and K. Bottomly. "Strength of TCR signal determines the costimulatory requirements for Th1 and Th2 CD4+ T cell differentiation." Journal of Immunology 159, no. 12 (December 15, 1997): 5956–63. http://dx.doi.org/10.4049/jimmunol.159.12.5956.

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Abstract Differentiation of naive CD4 T cells into cytokine-secreting effector Th1 and Th2 cells is influenced by several factors. We have previously reported that the affinity of antigen for TCR and antigen dose can influence the differentiation of Th1 and Th2 cells. Several in vitro and in vivo models have demonstrated a role for the costimulatory molecules, B7-1 (CD80) and B7-2 (CD86), in the generation of distinct effector T cell responses. To determine whether the strength of TCR signaling controls the involvement of CD28 costimulation in selective CD4 T cell differentiation, naive CD4 T cells bearing a transgenic TCR are primed by a weak or strong TCR signal (signal 1) in the presence or absence of B7 costimulatory molecules (signal 2). In this system, IL-4-producing Th2 cells are generated by priming with a weak but not a strong TCR signal. Th2 cell differentiation is dependent on CD28/B7 interactions in that disruption of CD28/B7 interactions inhibits the priming of Th2 cells and cross-linking CD28 with anti-CD28 antibody augments the priming of Th2 cells. In contrast, however, IL-4-producing Th2 cells cannot be generated by priming with a strong TCR signal even in the presence of strong costimulation or high doses of IL-2. Thus, our results suggest that naive CD4 T cells are receptive to CD28-dependent IL-4 production only if they receive a weak TCR signal.

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31

Lee, hee kyung, Hyunsu Bae, and namhee park. "Atractylodes japonica enhances CD4+ T-cell activities and modulates Th1/Th2 differentiation (90.8)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S158. http://dx.doi.org/10.4049/jimmunol.178.supp.90.8.

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Abstract Atractylodes japonica (AJ) is a common used herbal medicine in Asian countries such as Korea, China and Japan. The present study was designated to evaluate the direct effects of AJ on helper T cell activities and on Th1/Th2 lineage development in vitro. The results demonstrated that AJ had no mitogenic effects on unstimulated CD4+ T cells, but augmented CD4+ T-cell proliferation upon activation with anti-CD3/anti-CD28 antibodies in a dose-dependent manner. AJ treatment significantly increased CD4+T cell population and the IFN-γ expression was significantly enhanced, while IL-4 expression was significantly decreased. In addition, in vitro Th1/Th2 polarization experiments revealed that AJ enhanced IFN-γ secretion in Th1 cells, but reduced the IL-4 in Th2 cells in dose-dependent manner. Therefore, these results suggest that AJ treatment could be a desirable alternative therapy for the prevention or correction of Th2 dominant pathological disorders, such as allergy and asthma.

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Kumar, Sudhir, and Atin Adhikari. "Dose-dependent immunomodulating effects of endotoxin in allergic airway inflammation." Innate Immunity 23, no. 3 (January 31, 2017): 249–57. http://dx.doi.org/10.1177/1753425917690443.

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How very high exposure levels to endotoxin in a farming environment provide protection against respiratory allergic symptoms and low-to-moderate levels of endotoxin in urban homes promote allergic response is unclear. Dose-specific bacterial endotoxin or LPS-induced tolerance mechanisms can affect lung inflammations, coupled with the Th2 immune responses. Here, we explored the effects of intranasal exposure of LPS at two different doses (based on occupational exposures during handling of agricultural wastes) in OVA-sensitized allergic wild type (WT) and TLR4-KO mice, particularly, with respect to Th2 cytokines and Tregs level. Low-dose LPS (100 ng) exposure prohibited airway tolerance and failed to generate T-cell-dependent protection against lung inflammations in allergic mice. Furthermore, low Tregs at the inflammatory site and induced Th2 cytokines, as well as IL-6 and IL-25, suggested that low-dose LPS might be associated with the suppression of tolerance mechanisms. In contrast, high-dose LPS (20 µg) favored the suppression of Th2 cytokines, IL-6 and IL-25, but failed to induce Th1 cytokines (e.g. IFN-γ). Our results suggest that low-dose LPS can enhance airway allergic inflammation through failing of antigen-dependent immune regulatory homeostasis. The exposure levels of LPS can determine the generation of inflammatory responses in airway allergy.

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Hammad, Hamida, Maud Plantinga, Kim Deswarte, Philippe Pouliot, Monique A. M. Willart, Mirjam Kool, Femke Muskens, and Bart N. Lambrecht. "Inflammatory dendritic cells—not basophils—are necessary and sufficient for induction of Th2 immunity to inhaled house dust mite allergen." Journal of Experimental Medicine 207, no. 10 (September 6, 2010): 2097–111. http://dx.doi.org/10.1084/jem.20101563.

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It is unclear how Th2 immunity is induced in response to allergens like house dust mite (HDM). Here, we show that HDM inhalation leads to the TLR4/MyD88-dependent recruitment of IL-4 competent basophils and eosinophils, and of inflammatory DCs to the draining mediastinal nodes. Depletion of basophils only partially reduced Th2 immunity, and depletion of eosinophils had no effect on the Th2 response. Basophils did not take up inhaled antigen, present it to T cells, or express antigen presentation machinery, whereas a population of FceRI+ DCs readily did. Inflammatory DCs were necessary and sufficient for induction of Th2 immunity and features of asthma, whereas basophils were not required. We favor a model whereby DCs initiate and basophils amplify Th2 immunity to HDM allergen.

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Tan, Anna Marie, and Kim Bottomly. "Toll-like receptor 4 signaling in lung dendritic cells is required for the induction of T helper cell type 1 responses but dispensable for type 2 (B105)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): LB22. http://dx.doi.org/10.4049/jimmunol.178.supp.b105.

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Abstract We have previously reported that in a mouse model of allergic sensitization, low level inhaled LPS (LPSlow) signaling through TLR4 was necessary to induce Th2 responses while high level LPS (LPShigh) induced Th1 responses to inhaled antigen. The mechanism by which LPS signaling resulted in Th2 sensitization involved the activation of antigen-containing dendritic cells (DC). It remains unclear whether induction of these responses is dependent on TLR signaling in DCs, other lung cells, or in both. Here we report that antigen/LPShigh sensitized chimeric mice specifically lacking TLR4 signaling in the hematopoietic compartment (HPC) but sufficient for TLR4 in the stromal compartment (SC+HPC-) do not mount Th1 responses following antigen challenge while SC-HPC+ mice do. Strikingly, however, SC+HPC- mice mount exaggerated Th2 responses. Stromal TLR4 signaling in SC+HPC- mice leads to upregulation of the Th2-inducing Notch ligand Jagged-1 in DCs but not the Th1-inducing ligand Delta-4. In coculture, DCs activated by the stromal response to LPS polarize naïve antigen specific CD4 T cells to produce Th2 cytokines. These studies demonstrate that the TLR4-mediated response of stromal cells, through conditioning of DCs, is sufficient to induce robust allergic inflammatory responses to inhaled antigen containing LPS and define a novel role for lung stromal cells in the TLR4-dependent induction of allergic Th2 responses.

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Kono, Dwight H., Dimitri Balomenos, Deborah L. Pearson, Miyo S. Park, Bernhard Hildebrandt, Per Hultman та K. Michael Pollard. "The Prototypic Th2 Autoimmunity Induced by Mercury Is Dependent on IFN-γ and Not Th1/Th2 Imbalance". Journal of Immunology 161, № 1 (1 липня 1998): 234–40. http://dx.doi.org/10.4049/jimmunol.161.1.234.

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Abstract Imbalances of Th1- and Th2-type responses have been postulated to be a predisposing factor for both humoral and cellular mediated autoimmune diseases. To further define their roles in systemic autoimmunity, IL-4 and IFN-γ gene knockout mice were studied for susceptibility to the prototypic Th2-mediated mercury-induced autoimmunity. A predominant Th2-type response following HgCl2 treatment of wild-type B10.S mice was confirmed by the findings of a significant increase in splenic IL-4 and hypergammaglobulinemia primarily of the IgG1 isotype, without an increase in IFN-γ levels. Paradoxically, IL-4-deficient mice developed the characteristic anti-nucleolar autoantibodies and tissue deposition of immune complexes, while IFN-γ-deficient mice had very low autoantibody levels and essentially normal immunohistology. Studies to define defects in Ab responses of IFN-γ-deficient mice, using the T-dependent Ag (4-hydroxy-3-nitrophenyl)acetyl, revealed an attenuated IgG response to low and to a lesser extent high doses of (4-hydroxy-3-nitrophenyl)acetyl-hemocyanin, but maintenance of affinity maturation. These results indicate that Th1/Th2 imbalance does not directly play a role in susceptibility to mercury-induced autoimmunity, and suggest that the dependence on Th1-type responses in certain autoimmune diseases is due to the requirement for IFN-γ for Ab production to weakly antigenic self molecules.

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Leon-Cabrera, Sonia, and Ana Flisser. "Are Basophils Important Mediators for Helminth-Induced Th2 Immune Responses? A Debate." Journal of Biomedicine and Biotechnology 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/274150.

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Анотація:

Helminth parasites induce Th2 immune responses. Immunological mechanisms leading to Th2 induction are mainly dependent on IL-4. However, early source of IL-4 has not been precisely identified. Noticeably, basophils seem to be important mediators for inducing and maintaining the Th2 response probably because they secrete IL-4 and exert functions similar to APCs. Nevertheless, recent experimental evidence points that DCs could be also significant participants during this process. The involvement of basophils during memory responses is also discussed.

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Pedroza-Gonzalez, Alexander, Kangling Xu, Te-Chia Wu, Caroline Aspord, Sasha Tindle, Florentina Marches, Michael Gallegos, et al. "Thymic stromal lymphopoietin fosters human breast tumor growth by promoting type 2 inflammation." Journal of Experimental Medicine 208, no. 3 (February 21, 2011): 479–90. http://dx.doi.org/10.1084/jem.20102131.

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The human breast tumor microenvironment can display features of T helper type 2 (Th2) inflammation, and Th2 inflammation can promote tumor development. However, the molecular and cellular mechanisms contributing to Th2 inflammation in breast tumors remain unclear. Here, we show that human breast cancer cells produce thymic stromal lymphopoietin (TSLP). Breast tumor supernatants, in a TSLP-dependent manner, induce expression of OX40L on dendritic cells (DCs). OX40L+ DCs are found in primary breast tumor infiltrates. OX40L+ DCs drive development of inflammatory Th2 cells producing interleukin-13 and tumor necrosis factor in vitro. Antibodies neutralizing TSLP or OX40L inhibit breast tumor growth and interleukin-13 production in a xenograft model. Thus, breast cancer cell–derived TSLP contributes to the inflammatory Th2 microenvironment conducive to breast tumor development by inducing OX40L expression on DCs.

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Singh, R. R., B. H. Hahn, and E. E. Sercarz. "Neonatal peptide exposure can prime T cells and, upon subsequent immunization, induce their immune deviation: implications for antibody vs. T cell-mediated autoimmunity." Journal of Experimental Medicine 183, no. 4 (April 1, 1996): 1613–21. http://dx.doi.org/10.1084/jem.183.4.1613.

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Анотація:

Neonatal exposure to antigen is believed to result in T cell clonal inactivation or deletion. Here we report that, contrary to this notion, neonatal injection of BALB/c mice with a hen egg lysozyme peptide 106-116 in putative "tolergenic" doses induced a T cell proliferative and an immunoglobulin G (IgG) antibody (Ab) response of both T helper cell 1 (Th1)- (IgG2a, IgG2b, and IgG 3) and Th2-dependent (IgG1) isotopes. Upon subsequent challenge with the peptide in complete Freund's adjuvant in adult life, although this neonatal regimen suppressed proliferation and the production of Th1 cytokines (interleukin[IL]-2 and interferon gamma), Th2 cytokine (IL-5, IL-4, and IL-10) secretion was increased, and the serum levels of Th1- and Th2-dependent isotypes of peptide-specific Ab remained elevated. The in vitro proliferative unresponsiveness in Th1 cells could be reversed by Abs to Th2 cytokines (IL-4 and IL-10). Thus, neonatal treatment with a peptide antigen induces T cell priming including production of IgG Abs of both Th1- and Th2-dependent isotypes. Upon subsequent peptide exposure, the peptide-specific T cell responses undergo an effective class switch in the direction of Th2, resulting in T cell proliferative unresponsiveness. Accordingly, this shift towards increased Ab production to autoantigen could be deleterious in individuals prone to antibody-mediated diseases. Indeed, neonatal treatment with a self-autoantigenic peptide from an anti-DNA monoclonal Ab (A6H 58-69) significantly increased the IgG anti-double-stranded DNA Ab levels in lupus-prone NZB/NZW F1 mice, despite suppressing peptide-specific T cell proliferation. This adverse clinical response is in sharp contrast to the beneficial outcome of neonatal treatment with autoantigens in Th1-mediated autoimmune diseases, such as autoimmune encephalomyelitis, as reported by others. A Th1 to Th2 immune deviation can explain the discordant biological responses after the presumed induction of neonatal tolerance in autoantibody- vs. Th-1 mediated autoimmune diseases.

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Ranganath, Sheila, and Kenneth M. Murphy. "Structure and Specificity of GATA Proteins in Th2 Development." Molecular and Cellular Biology 21, no. 8 (April 15, 2001): 2716–25. http://dx.doi.org/10.1128/mcb.21.8.2716-2725.2001.

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ABSTRACT Development of Th2 subset of CD4+ T cells involves the interleukin-4 (IL-4)- and Stat6-dependent increase in GATA-3 expression during primary activation. Recently we reported that the phenotypic stability and factor independence of Th2 cells involves acquisition of an intracellular pathway that maintains GATA-3 expression. Evidence from retroviral expression studies implied that this pathway involved an autoactivation of GATA-3 expression, since Stat6-deficient T cells induced endogenous GATA-3 when infected with GATA-3-expressing retroviruses. That study left unresolved the issue of whether GATA-3 autoactivation was direct or indirect. Several other Th2-specific transcription factors have been described, including c-Maf and JunB. We therefore examined the ability of these other transcription factors to induce GATA-3 expression and promote Th2 development. Neither c-Maf nor JunB induced Th2 development in Stat6-deficient CD4+ T cells, in contrast to GATA-3. Consistent with this indication of a possible direct autoactivation pathway, we also observed that heterologous GATA family proteins GATA-1, GATA-2, and GATA-4 were also capable of inducing GATA-3 expression in developing Stat6-deficient T cells and promote Th2 development. Mutational analysis revealed evidence for two distinct mechanisms of GATA-3 action. IL-4 induction by GATA-3 required each of the functional domains to be present, whereas repression of gamma interferon could occur even when mutants of GATA-3 lacking the second transactivation domain, TA2, were expressed. The GATA-dependent induction of the GATA-3 but not the other GATA genes in T cells suggests that T-cell-specific cis elements within the GATA-3 locus likely cooperate with a general GATA recognition motif to allow GATA-3-dependent autoactivation.

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40

Bonecchi, Raffaella, Silvano Sozzani, Johnny T. Stine, Walter Luini, Giovanna D’Amico, Paola Allavena, David Chantry та Alberto Mantovani. "Divergent Effects of Interleukin-4 and Interferon-γ on Macrophage-Derived Chemokine Production: An Amplification Circuit of Polarized T Helper 2 Responses". Blood 92, № 8 (15 жовтня 1998): 2668–71. http://dx.doi.org/10.1182/blood.v92.8.2668.

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Анотація:

Abstract Macrophage-derived chemokine (MDC) is a CC chemokine that recognizes the CCR4 receptor and is selective for T helper 2 (Th2) versus T helper 1 (Th1) cells. The present study was designed to investigate the effect of the prototypic Th2/Th1 cytokines, interleukin-4 (IL-4) and interferon-γ (IFN-γ), on the production of MDC by human monocytes. IL-4 and IL-13 caused a time-dependent (plateau at 24 hours) and concentration-dependent (EC50 2 and 10 ng/mL, respectively) increase of MDC mRNA levels in monocytes. Increased expression of MDC mRNA was associated with protein release in the supernatant. MDC expression and production induced by IL-4 and IL-13 were inhibited by IFN-γ. IFN-γ also suppressed the constitutive expression of MDC in mature macrophages and dendritic cells. These results delineate an amplification loop of polarized Th2 responses based on differential regulation of MDC production by IL-4 and IL-13 versus IFN-γ and on the selectivity of this chemokine for polarized Th2 cells. © 1998 by The American Society of Hematology.

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Bonecchi, Raffaella, Silvano Sozzani, Johnny T. Stine, Walter Luini, Giovanna D’Amico, Paola Allavena, David Chantry та Alberto Mantovani. "Divergent Effects of Interleukin-4 and Interferon-γ on Macrophage-Derived Chemokine Production: An Amplification Circuit of Polarized T Helper 2 Responses". Blood 92, № 8 (15 жовтня 1998): 2668–71. http://dx.doi.org/10.1182/blood.v92.8.2668.420k39_2668_2671.

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Анотація:

Macrophage-derived chemokine (MDC) is a CC chemokine that recognizes the CCR4 receptor and is selective for T helper 2 (Th2) versus T helper 1 (Th1) cells. The present study was designed to investigate the effect of the prototypic Th2/Th1 cytokines, interleukin-4 (IL-4) and interferon-γ (IFN-γ), on the production of MDC by human monocytes. IL-4 and IL-13 caused a time-dependent (plateau at 24 hours) and concentration-dependent (EC50 2 and 10 ng/mL, respectively) increase of MDC mRNA levels in monocytes. Increased expression of MDC mRNA was associated with protein release in the supernatant. MDC expression and production induced by IL-4 and IL-13 were inhibited by IFN-γ. IFN-γ also suppressed the constitutive expression of MDC in mature macrophages and dendritic cells. These results delineate an amplification loop of polarized Th2 responses based on differential regulation of MDC production by IL-4 and IL-13 versus IFN-γ and on the selectivity of this chemokine for polarized Th2 cells. © 1998 by The American Society of Hematology.

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Fang, Difeng, Kairong Cui, Gangqing Hu, Rama Krishna Gurram, Chao Zhong, Andrew J. Oler, Ryoji Yagi, et al. "Bcl11b, a novel GATA3-interacting protein, suppresses Th1 while limiting Th2 cell differentiation." Journal of Experimental Medicine 215, no. 5 (March 7, 2018): 1449–62. http://dx.doi.org/10.1084/jem.20171127.

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GATA-binding protein 3 (GATA3) acts as the master transcription factor for type 2 T helper (Th2) cell differentiation and function. However, it is still elusive how GATA3 function is precisely regulated in Th2 cells. Here, we show that the transcription factor B cell lymphoma 11b (Bcl11b), a previously unknown component of GATA3 transcriptional complex, is involved in GATA3-mediated gene regulation. Bcl11b binds to GATA3 through protein–protein interaction, and they colocalize at many important cis-regulatory elements in Th2 cells. The expression of type 2 cytokines, including IL-4, IL-5, and IL-13, is up-regulated in Bcl11b-deficient Th2 cells both in vitro and in vivo; such up-regulation is completely GATA3 dependent. Genome-wide analyses of Bcl11b- and GATA3-regulated genes (from RNA sequencing), cobinding patterns (from chromatin immunoprecipitation sequencing), and Bcl11b-modulated epigenetic modification and gene accessibility suggest that GATA3/Bcl11b complex is involved in limiting Th2 gene expression, as well as in inhibiting non-Th2 gene expression. Thus, Bcl11b controls both GATA3-mediated gene activation and repression in Th2 cells.

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Perrigoue, Jacqueline G., Steven A. Saenz, Mark C. Siracusa, Eric J. Allenspach, Betsy C. Taylor, Paul R. Giacomin, Meera G. Nair, et al. "MHC class II–dependent basophil–CD4+ T cell interactions promote TH2 cytokine–dependent immunity." Nature Immunology 10, no. 7 (May 24, 2009): 697–705. http://dx.doi.org/10.1038/ni.1740.

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Coyle, Anthony J., and Shogo Tsuyuki. "Th2 cells and cytokine networks in allergic inflammation of the lung." Mediators of Inflammation 4, no. 4 (1995): 239–47. http://dx.doi.org/10.1155/s096293519500038x.

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The cytokines released from Th2 and Th2-like cells are likely to be central to the pathophysiolgy of asthma and allergy, contributing to aberrant IgE production, eosinophilia and, perhaps, mucosal susceptibility to viral infection. IL-4 has emerged as a central target, not only for B cell IgE production, but also in the commitment of both CD4+ and CD8+ T cells to cells with Th2 effector function capable of secreting IL-5 resultlng in eosinophilic inflammation. In view of the central role of this cytokine and the evidence that glucocorticoids are unable to modify many IL-4 dependent effects, Th2 inhibitors may prove to be novel therapies for the treatment of bronchial asthma.

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45

Cook, Kevin D., and Jim Miller. "TCR-Dependent Translational Control of GATA-3 Enhances Th2 Differentiation." Journal of Immunology 185, no. 6 (August 9, 2010): 3209–16. http://dx.doi.org/10.4049/jimmunol.0902544.

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46

Brunetti, Natale Daniele, Martino Pepe, Irene Munno, Fabio Tiecco, Donato Quagliara, Luisa De Gennaro, Antonio Gaglione, Matteo Di Biase, and Stefano Favale. "Th2-dependent cytokine release in patients treated with coronary angioplasty." Coronary Artery Disease 19, no. 3 (May 2008): 133–37. http://dx.doi.org/10.1097/mca.0b013e3282f3fbcb.

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47

Tordesillas, Leticia, Ritobrata Goswami, Sara Benedé, Galina Grishina, David Dunkin, Kirsi M. Järvinen, Soheila J. Maleki, Hugh A. Sampson, and M. Cecilia Berin. "Skin exposure promotes a Th2-dependent sensitization to peanut allergens." Journal of Clinical Investigation 124, no. 11 (October 8, 2014): 4965–75. http://dx.doi.org/10.1172/jci75660.

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48

Iwamura, C., M. Y. Kimura, K. Shinoda, Y. Endo, A. Hasegawa, M. Yamashita, and T. Nakayama. "Schnurri-2 regulates Th2-dependent airway inflammation and airway hyperresponsiveness." International Immunology 19, no. 6 (May 9, 2007): 755–62. http://dx.doi.org/10.1093/intimm/dxm042.

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Swaidani, Shadi, Katarzyna Bulek, Zizhen Kang, Caini Liu, Yi Lu, Mark Aronica, and Xiaoxia Li. "287 ACT1 is required for IL-25-dependent TH2 responses." Cytokine 43, no. 3 (September 2008): 311. http://dx.doi.org/10.1016/j.cyto.2008.07.369.

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50

Piggott, Damani A., Stephanie C. Eisenbarth, Lan Xu, Stephanie L. Constant, James W. Huleatt, Christina A. Herrick, and Kim Bottomly. "MyD88-dependent induction of allergic Th2 responses to intranasal antigen." Journal of Clinical Investigation 115, no. 2 (January 13, 2005): 459–67. http://dx.doi.org/10.1172/jci200522462.

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