Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TGF-beta plays an important role in immune regulation in vivo and affects T cell differentiation in vitro. Here we describe how TGF-beta modulates Th2 development in vitro and investigate its mechanisms of action. TGF-beta down-regulated Th2 development of naive CD4+ Mel-14high T cells derived from the DO11.10 ovalbumin-specific TCR-transgenic mouse, and this was observed both in cultures driven with anti-CD3 and anti-CD28 and with splenic APC and antigen. TGF-beta down-regulated GATA-3 expression in developing Th2 and these cells showed a diminished IL-4-induced STAT6 activation. We found, however, that naive cells driven in Th2 conditions with TGF-beta did not show a significantly decreased STAT6 activation, suggesting that TGF-beta inhibits Th2 development via a STAT6-independent mechanism.
 ...
PMID:TGF-beta1 down-regulates Th2 development and results in decreased IL-4-induced STAT6 activation and GATA-3 expression. 1100 98

1alpha,25-Dihydroxyvitamin D3 (vitD3) is an immunoregulatory hormone with beneficial effects on Th1 mediated autoimmune diseases. Although the inhibitory effects of vitD3 on macrophages and dendritic cells are well documented, any direct effects of vitD3 on Th cell development are not clearly defined. Using CD4(+)Mel14(+) T cells derived from mice on a BALB/c and a C57BL/6 genetic background we examined the effect of vitD3 on Th cell development. We demonstrated that vitD3 affects Th cell polarization by inhibiting Th1 (IFN-gamma production) and augmenting Th2 cell development (IL-4, IL-5, and IL-10 production). These effects were observed in cultures driven with splenic APC and Ag, as well as with anti-CD3 and anti-CD28 alone, indicating that CD4(+) cells can also be direct targets for vitD3. The enhanced Th2 development by vitD3 was found in both BALB/c and C57BL/6 mice. An increased expression of the Th2-specific transcription factors GATA-3 and c-maf correlated with the increased production of Th2 cytokines after vitD3 treatment. The vitD3-induced effects were largely mediated via IL-4, because neutralization of IL-4 almost completely abrogated the augmented Th2 cell development after vitD3 treatment. These findings suggest that vitD3 acts directly on Th cells and can, in the absence of APC, enhance the development of a Th2 phenotype and augment the expression of the transcription factors c-maf and GATA-3. Our findings suggest that the beneficial effects of vitD3 in autoimmune diseases and transplantation operate through prevention of strong Th1 responses via the action on the APC, while simultaneously directly acting on the T cell to enhance Th2 cell development.
 ...
PMID:1alpha,25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells. 1167 4

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or statins are newly identified immunomodulators. In vivo treatment of SJL/J mice with lovastatin reduced the duration and clinical severity of active and passive experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Lovastatin induced the expression of GATA3 and the phosphorylation of STAT6, whereas it inhibited tyrosine phosphorylation of Janus kinase 2, tyrosine kinase 2, and STAT4. Inhibition of the Janus kinase-STAT4 pathway by lovastatin modulated T0 to Th1 differentiation and reduced cytokine (IFN-gamma and TNF-alpha) production, thus inducing Th2 cytokines (IL-4, IL-5, and IL-10). It inhibited T-bet (T box transcription factor) and NF-kappaB in activated T cells and significantly reduced infiltration of CD4- and MHC class II-positive cells to CNS. Further, it stabilized IL-4 production and GATA-3 expression in differentiated Th2 cells, whereas in differentiated Th1 cells it inhibited the expression of T-bet and reduced the production of IFN-gamma. Moreover, lovastatin-exposed macrophage and BV2 (microglia) in allogeneic MLRs induced the production of the anti-inflammatory cytokine IL-10. These observations indicate that the anti-inflammatory effects of lovastatin are mediated via T cells as well as APCs, because it modulates the polarization patterns of naive T cell activation in an APC-independent system. Together, these findings reveal that lovastatin may have possible therapeutic value involving new targets (in both APCs and T cells) for the treatment of multiple sclerosis and other inflammatory diseases.
 ...
PMID:Potential targets of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor for multiple sclerosis therapy. 1470 6

Differentiation of uncommitted T cells into Th1 and Th2 subpopulations depends on both intracellular events controlling expression of transcription factors T-bet and GATA-3 and interactions between cells mediated by cytokines, particularly IL4 and IFNgamma. A great deal is known about the intracellular and extracellular events involved in Th1 and Th2 (Th) differentiation, but how these are integrated in T-cell populations or indeed why extracellular cytokine control is required after a decision has been made at a transcriptional level is not at all understood. We present a mathematical model of CD4+ T-cell differentiation that describes both intracellular and extracellular processes and the interactions between them. It shows how antigen stimulation in conjunction with cytokines and other extracellular signals gives rise to rapid, reversible and mutually exclusive expression of T-bet or GATA-3 due to feedback between the transcription factors and their signalling pathways. After transient signalling by APC, continued Th1 and Th2 differentiation is shown to require cytokine production by the proliferating T cells. Moreover, intercellular communication by T-cell-derived cytokines lowers the threshold of APC signals required for Th differentiation. This provides an explanation for enhanced Th differentiation by pre-existing memory T cells. The model also predicts that Th differentiation can be reversed at the single cell level before commitment by manipulating the cytokine environment. It suggests a mechanism for switching between Th1 and Th2 in the so-called irreversible state that may be developed as a novel therapeutic means of manipulating Th1 and Th2 responses.
 ...
PMID:Combining cytokine signalling with T-bet and GATA-3 regulation in Th1 and Th2 differentiation: a model for cellular decision-making. 1538 Mar 83

The effects of 17beta-estradiol (E2) on immune function have been extensively reported. The effects are dependent on concentration and duration of exposure and potential differences in signaling between the known E2 receptors, estrogen receptors (ER) alpha and ERbeta. Through the use of ER-deficient mice, we and others have begun to demonstrate the role of the two known receptors in modulating immune functional activities. Previous studies have shown that cells of the innate immune system have altered function (bactericidal capacity) and patterns of cytokine expression (increased proinflammatory cytokine expression) through amelioration of ERalpha signaling. In this study, we extend these studies to analysis of T cell differentiation and proliferation in APC-dependent and APC-independent in vitro assay systems. Our results demonstrate that ERalpha deficiency in splenic macrophages, but not CD11c+ splenic dendritic cells pulsed with OVA significantly enhances proliferative responses and IFN-gamma production by transgenic OVA peptide-specific (OT-II) CD4+ T cells when compared with Ag-pulsed APC from wild-type littermates. The addition of E2 in this culture system did not significantly affect the production of IFN-gamma. In addition, when purified CD4+ T cells from ERalpha-deficient and wild-type littermates were stimulated with anti-CD3/CD28 Ab in the absence of E2, there were no significant differences in IFN-gamma or IL-4 production. However, the addition of E2 significantly increased IL-4 secretion, as well as increased GATA-3 mRNA levels from ERalpha-replete CD4+ T cells, while this effect was abrogated in ERalpha-deficient CD4+ T cells.
 ...
PMID:Estrogen receptor alpha (ERalpha) deficiency in macrophages results in increased stimulation of CD4+ T cells while 17beta-estradiol acts through ERalpha to increase IL-4 and GATA-3 expression in CD4+ T cells independent of antigen presentation. 1623 62

The adjuvanticity of bacterial adenylate cyclase toxins has been ascribed to their capacity, largely mediated by cAMP, to modulate APC activation, resulting in the expression of Th2-driving cytokines. On the other hand, cAMP has been demonstrated to induce a Th2 bias when present during T cell priming, suggesting that bacterial cAMP elevating toxins may directly affect the Th1/Th2 balance. Here we have investigated the effects on human CD4(+) T cell differentiation of two adenylate cyclase toxins, Bacillus anthracis edema toxin (ET) and Bordetella pertussis CyaA, which differ in structure, mode of cell entry, and subcellular localization. We show that low concentrations of ET and CyaA, but not of their genetically detoxified adenylate cyclase defective counterparts, potently promote Th2 cell differentiation by inducing expression of the master Th2 transcription factors, c-maf and GATA-3. We also present evidence that the Th2-polarizing concentrations of ET and CyaA selectively inhibit TCR-dependent activation of Akt1, which is required for Th1 cell differentiation, while enhancing the activation of two TCR-signaling mediators, Vav1 and p38, implicated in Th2 cell differentiation. This is at variance from the immunosuppressive toxin concentrations, which interfere with the earliest step in TCR signaling, activation of the tyrosine kinase Lck, resulting in impaired CD3zeta phosphorylation and inhibition of TCR coupling to ZAP-70 and Erk activation. These results demonstrate that, notwithstanding their differences in their intracellular localization, which result in focalized cAMP production, both toxins directly affect the Th1/Th2 balance by interfering with the same steps in TCR signaling, and suggest that their adjuvanticity is likely to result from their combined effects on APC and CD4(+) T cells. Furthermore, our results strongly support the key role of cAMP in the adjuvanticity of these toxins.
 ...
PMID:The adenylate cyclase toxins of Bacillus anthracis and Bordetella pertussis promote Th2 cell development by shaping T cell antigen receptor signaling. 1926 22

Antiinfluenza type 2 (T2) immunity contributes to both immunopathology and immunoprotection, yet the underlying mechanisms modulating T2 immunity remain ill defined. We describe a novel mouse antigen (Ag)-presenting cell (APC), designated late-activator APC (LAPC). After pulmonary influenza A (H1N1) virus infection, LAPCs enter the lungs, capture viral Ag, and subsequently migrate to the draining lymph node (DLN) and spleen, with delayed kinetics relative to dendritic cells (DCs). In the DLN, influenza virus-activated LAPCs present Ag and selectively induce T helper type 2 (Th2) effector cell polarization by cell-cell contact-mediated modulation of GATA-3 expression. In adoptive transfer experiments, influenza virus-activated LAPCs augmented Th2 effector T cell responses in the DLN, increased production of circulating antiinfluenza immunoglobulin, and increased levels of T2 cytokines in bronchoalveolar lavage fluid in recipient influenza virus-infected mice. LAPC-recipient mice exhibited exacerbated pulmonary pathology, with delayed viral clearance and enhanced pulmonary eosinophilia. Collectively, our results identify and highlight the importance of LAPCs as immunomodulators of T2 immunity during influenza A virus infection.
 ...
PMID:Identification of a novel antigen-presenting cell population modulating antiinfluenza type 2 immunity. 2054 25