Transcription mediated by NFAT is highly inducible in effector CD4+ T helper 2 (Th2) cells but not in Th1 cells.

Transcriptional factors of the NFAT family play an important role in regulating the expression of several cytokine genes during the immune response, such as the genes for interleukin 2 (IL-2) and IL-4, among others. Upon antigen stimulation, precursor CD4+ T helper (pTh) cells proliferate and differentiate into two populations of effector cells (eTh1 and eTh2), each one expressing a specific pattern of cytokines that distinguishes them from their precursors. eTh2 cells are the major source of IL-4, while gamma interferon is produced by eTh1 cells. Here we have used reporter transgenic mice to show that DNA binding and transcriptional activities of NFAT are transiently induced during the differentiation of pTh cells into either eTh1 or eTh2 cells to mediate the expression of IL-2 as a common growth factor in both pathways. However, although NFAT DNA binding is similarly induced in both eTh1 and eTh2 cells upon antigen stimulation, only the NFAT complexes present in eTh2 cells are able to mediate high-level transcription, and relatively little NFAT transcriptional activity was induced in eTh1 cells. In contrast to activated pTh cells, neither eTh1 nor eTh2 cells produced significant IL-2 upon stimulation, but the high levels of NFAT transcriptional activities directly correlate with the IL-4 production induced in response to antigen stimulation in eTh2 cells. These data suggest that activated NFAT is involved in the effector function of eTh2 cells and that the failure of eTh1 cells to produce IL-4 in response to an antigen is due, at least partially, to a failure to induce high-level transcription of the IL-4 gene by NFAT. Regulation of NFAT could be therefore a critical element in the polarization to eTh1 or eTh2.

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Experimental Leishmania infection: Generation of T-helper 2 (Th2) cells in susceptible and resistant mice?

Immunology Letters ◽

10.1016/s0165-2478(97)88569-0 ◽

1997 ◽

Vol 56 (1-3) ◽

pp. 426

Author(s):

F Sommer

Keyword(s):

Th2 Cells ◽

Leishmania Infection ◽

T Helper ◽

T Helper 2

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OX40 (CD134) Controls Memory T Helper 2 Cells that Drive Lung Inflammation

Journal of Experimental Medicine ◽

10.1084/jem.20021937 ◽

2003 ◽

Vol 198 (2) ◽

pp. 315-324 ◽

Cited By ~ 177

Author(s):

Shahram Salek-Ardakani ◽

Jianxun Song ◽

Beth S. Halteman ◽

Amha Gebre-Hiwot Jember ◽

Hisaya Akiba ◽

...

Keyword(s):

T Cells ◽

Memory T Cells ◽

Costimulatory Molecule ◽

Airway Hyperreactivity ◽

Th2 Cells ◽

T Helper ◽

Cd4 Cells ◽

T Helper 2 ◽

Large Numbers ◽

Draining Lymph Nodes

Asthma is caused by memory Th2 cells that often arise early in life and persist after repeated encounters with allergen. Although much is known regarding how Th2 cells develop, there is little information about the molecules that regulate memory Th2 cells after they have formed. Here we show that the costimulatory molecule OX40 is expressed on memory CD4 cells. In already sensitized animals, blocking OX40–OX40L interactions at the time of inhalation of aerosolized antigen suppressed memory effector accumulation in lung draining lymph nodes and lung, and prevented eosinophilia, airway hyperreactivity, mucus secretion, and Th2 cyto-kine production. Demonstrating that OX40 signals directly regulate memory T cells, antigen-experienced OX40-deficient T cells were found to divide initially but could not survive and accumulate in large numbers after antigen rechallenge. Thus, OX40–OX40L interactions are pivotal to the efficiency of recall responses regulated by memory Th2 cells.

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Interleukin-2 Family Members and their Role in Demyelinating Disease

Annals of Immunology & Immunotherapy ◽

10.23880/aii-16000125 ◽

2020 ◽

Vol 2 (2) ◽

Author(s):

: Mahendra K Bhopale

Keyword(s):

T Cells ◽

Demyelinating Disease ◽

Cytotoxic T Cells ◽

Interleukin 2 ◽

Th2 Cells ◽

T Helper ◽

Th1 Cell ◽

Memory Cd8 T Cells ◽

Regulatory Effects ◽

Negative Regulatory Role

Interleukin-2 (IL-2) has a family which includes IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 cytokines. This family group of an IL-2 cytokine plays important, but different roles in neurologically related demyelinating disease studied in multiple sclerosis (MS) and it’s experimentally induced rodent models. IL-2 play role in strong T-cell expansion and participates in the maintenance of T-regs cells, but also keep in the stimulation and proliferation of pathogenic T cells. IL-4 induces differentiation of naïve helper T cells (Th0) to Th2 cells. IL-7 promotes Th1 cell differentiation. IL-9 is a hematopoietic growth factor for major pathogenic Th17 cells in EAE. IL-15 is necessary for memory CD8+ T cells and plays a negative regulatory role through CD8+ CD122+ T cells in reducing Th17-mediated inflammation. IL-21 has potent regulatory effects on the natural killer (NK) cells and cytotoxic T cells. IL-21 activates CD4+ and up-regulates the Th2 and Th17 subsets of T helper cells. Based on different roles of each family member in demyelinating disease, bio-agents and therapeutic agents have been attempted in an experimental model to study their role in demyelinating disease is described in the present review.

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T Helper 2 (Th2) Cells

Encyclopedia of Immunotoxicology ◽

10.1007/978-3-642-54596-2_201436 ◽

2015 ◽

pp. 868-868

Keyword(s):

Th2 Cells ◽

T Helper ◽

T Helper 2

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Selective disruption of interleukin 4 autocrine-regulated loop by a tyrosine kinase inhibitor restricts activity of T-helper 2 cells

Blood ◽

10.1182/blood.v95.12.3816.012k29_3816_3822 ◽

2000 ◽

Vol 95 (12) ◽

pp. 3816-3822 ◽

Cited By ~ 2

Author(s):

Li Hua Wang ◽

Robert A. Kirken ◽

Xiao Yi Yang ◽

Rebecca A. Erwin ◽

Luis DaSilva ◽

...

Keyword(s):

Tyrosine Kinase ◽

Cell Line ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Inhibitory Effect ◽

Interleukin 4 ◽

Th2 Cells ◽

T Helper ◽

Th1 Cell ◽

T Helper 2

Interleukin (IL) 4 is a potent immunomodulatory cytokine secreted by T-helper 2 (Th2) cells and Th2 mast cells that promotes the commitment of cells. However, unregulated production and release of IL-4 can exacerbate allergic reactions and increase susceptibility to infectious organisms and viruses. Here, we present evidence that AG-490, a Janus tyrosine kinase (JAK) 2-JAK3 inhibitor, effectively blocked IL-4 gene expression and secretion in the Th2 cell line D10 that was not occurring after anti-CD3 antibody stimulation, whereas AG-490 had no inhibitory effect on production of other Th2 cytokines or cytokines synthesized by the corresponding Th1 cell line clone 29. AG-490 potently inhibited IL-4–mediated proliferation of both D10 and the IL-4–dependent cell line CT.4S. Moreover, AG-490 markedly inhibited IL-4 activation of JAK3 and blocked the downstream activation of signal transducer and activator of transcription 6, as judged by tyrosine phosphorylation, DNA binding, and transcription assays. In contrast, AG-490 did not affect tumor necrosis factor  activation of NF-κB at similar concentrations of drug. These data suggest that tyrosine kinase inhibitors that inhibit JAK3 may have previously unrecognized and selective clinical potential as immunotherapeutic drugs to treat Th2-mediated diseases driven by IL-4.

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Immunosuppression byN-Methyl-d-Aspartate Receptor Antagonists Is Mediated through Inhibition of Kv1.3 and KCa3.1 Channels in T Cells

Molecular and Cellular Biology ◽

10.1128/mcb.01273-13 ◽

2013 ◽

Vol 34 (5) ◽

pp. 820-831 ◽

Cited By ~ 24

Author(s):

Sascha Kahlfuß ◽

Narasimhulu Simma ◽

Judith Mankiewicz ◽

Tanima Bose ◽

Theresa Lowinus ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Neuronal Development ◽

Cell Function ◽

Therapeutic Potential ◽

Interleukin 2 ◽

Cell Receptor ◽

Th2 Cells ◽

Effector Cells ◽

Ifn Γ

N-Methyl-d-aspartate receptors (NMDARs) are ligand-gated ion channels that play an important role in neuronal development, plasticity, and excitotoxicity. NMDAR antagonists are neuroprotective in animal models of neuronal diseases, and the NMDAR open-channel blocker memantine is used to treat Alzheimer's disease. In view of the clinical application of these pharmaceuticals and the reported expression of NMDARs in immune cells, we analyzed the drug's effects on T-cell function. NMDAR antagonists inhibited antigen-specific T-cell proliferation and cytotoxicity of T cells and the migration of the cells toward chemokines. These activities correlated with a reduction in T-cell receptor (TCR)-induced Ca2+mobilization and nuclear localization of NFATc1, and they attenuated the activation of Erk1/2 and Akt. In the presence of antagonists, Th1 effector cells produced less interleukin-2 (IL-2) and gamma interferon (IFN-γ), whereas Th2 cells produced more IL-10 and IL-13. However, in NMDAR knockout mice, the presumptive expression of functional NMDARs in wild-type T cells was inconclusive. Instead, inhibition of NMDAR antagonists on the conductivity of Kv1.3 and KCa3.1 potassium channels was found. Hence, NMDAR antagonists are potent immunosuppressants with therapeutic potential in the treatment of immune diseases, but their effects on T cells have to be considered in that Kv1.3 and KCa3.1 channels are their major effectors.

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Lymphokine-mediated regulation of the proliferative response of clones of T helper 1 and T helper 2 cells.

Journal of Experimental Medicine ◽

10.1084/jem.168.2.543 ◽

1988 ◽

Vol 168 (2) ◽

pp. 543-558 ◽

Cited By ~ 251

Author(s):

R Fernandez-Botran ◽

V M Sanders ◽

T R Mosmann ◽

E S Vitetta

Keyword(s):

Proliferative Response ◽

Th2 Cells ◽

Th1 Cells ◽

T Helper ◽

T Helper 1 ◽

Ifn Gamma ◽

T Helper 2 ◽

Regulatory Interactions ◽

Th Cell ◽

Th1 And Th2

Murine Th1 and Th2 subsets differ not only in the lymphokines they produce, but also functionally. It is not clear what factors influence the preferential activation of one subset versus the other and what regulatory interactions exist between them. The purpose of this study was to examine the effect of lymphokines produced by clones of Th1 cells (IL-2 and IFN-gamma), Th2 cells (IL-4), and APC (IL-1) on the proliferative response of Th1 and Th2 cells after antigenic stimulation. Activation of both types of clones in the presence of antigen and APC resulted in the acquisition of responsiveness to the proliferative effects of both IL-2 and IL-4, although Th2 cells were more responsive to IL-4 than Th1 cells. Responsiveness of Th1 and Th2 cells to both lymphokines decreased with time after initial antigenic activation; Th1 cells lost their responsiveness to IL-4 more rapidly and to IL-2 more slowly than Th2 cells. IFN-gamma partially inhibited the IL-2 and IL-4-mediated proliferation of Th2, but not Th1 cells. Although the presence of IL-1 was not required for the response of Th1 or Th2 cells to IL-4, its presence resulted in a synergistic effect with IL-2 or IL-4 in Th2 but not in Th1 cells. Both subsets responded to a mixture of IL-2 and IL-4 in synergistic fashion. Delayed addition and wash-out experiments indicated that both IL-2 and IL-4 had to be present simultaneously in order for synergy to occur. These results suggest that Th cell subsets might regulate each other via the lymphokines that they secrete and that the pathways of IL-2 and IL-4 mediated proliferation are interrelated.

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SOCS proteins in T helper cell differentiation: implications for allergic disorders?

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399404008348 ◽

2004 ◽

Vol 6 (22) ◽

pp. 1-11 ◽

Cited By ~ 12

Author(s):

Hiromasa Inoue ◽

Masato Kubo

Keyword(s):

Cell Differentiation ◽

Specific Ige ◽

Th2 Cells ◽

T Helper ◽

T Helper 2 ◽

Th Cell ◽

Socs Proteins ◽

Th2 Differentiation ◽

Allergic Disorders

Asthma, allergic rhinitis and atopic dermatitis are allergic immune disorders characterised by a predominance of T helper 2 (Th2) cells, the resulting elevation of allergen-specific IgE, and mast-cell- and basophil-associated inflammation. The cytokine environment at the site of the initial antigen stimulation determines the direction of Th-cell differentiation into Th1 or Th2 cells. The SOCS (suppressor of cytokine signalling) proteins are implicated in the control of the balance between Th1 and Th2 cells in this process. SOCS3 is predominantly expressed in Th2 cells and inhibits Th1 differentiation; conversely, SOCS5 is expressed predominantly in Th1 cells and inhibits Th2 differentiation. Here, we discuss the role of SOCS proteins in Th-cell differentiation and explore the potential of SOCS proteins as targets for therapeutic strategies in allergic disorders.

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