Ephrin-A1 suppresses Th2 cell activation and provides a regulatory link to lung epithelial cells.

Gene expression screening showed decreased ephrin-A1 expression in CD4+ T cells of asthma patients. Ephrin-A1 is the ligand of the Eph receptor family of tyrosine kinases, forming the largest family of receptor tyrosine kinases. Their immune regulatory properties are largely unknown. This study demonstrates significantly reduced ephrin-A1 expression in T cells of asthma patients using real time-PCR. Immunohistological analyses revealed strong ephrin-A1 expression in lung tissue and low expression in cortical areas of lymph nodes. It is absent in T cell/B cell areas of the spleen. Colocalization of ephrin-A1 and its receptors was found only in the lung, but not in lymphoid tissues. In vitro activation of T cells reduced ephrin-A1 at mRNA and protein levels. T cell proliferation, activation-induced, and IL-2-dependent cell death were inhibited by cross-linking ephrin-A1, and not by engagement of Eph receptors. However, anti-EphA1 receptor slightly enhances Ag-specific and polyclonal proliferation of PBMC cultures. Furthermore, activation-induced CD25 up-regulation was diminished by ephrin-A1 engagement. Ephrin-A1 engagement reduced IL-2 expression by 82% and IL-4 reduced it by 69%; the IFN-gamma expression remained unaffected. These results demonstrate that ephrin-A1 suppresses T cell activation and Th2 cytokine expression, while preventing activation-induced cell death. The reduced ephrin-A1 expression in asthma patients may reflect the increased frequency of activated T cells in peripheral blood. That the natural ligands of ephrin-A1 are most abundantly expressed in the lung may be relevant for Th2 cell regulation in asthma and Th2 cell generation by mucosal allergens.

T cell phenotype in allergic asthma and atopic dermatitis.

BACKGROUND: T cells are key regulators of immunologic disease parameters. However, their contribution to the process of tissue remodeling is ill defined. In the present study, we investigated gene expression of allergy-characteristic, IL-4-rich T cell cDNAs to monitor expression of genes that might participate in the pathogenesis of allergic diseases. METHODS: cDNAs of freshly isolated and restimulated CD4+ T cells from patients with allergic asthma (AA) or atopic dermatitis (AD) and healthy subjects were analyzed on Nylon membrane-based DNA arrays. Three patients were selected for an allergy-characteristic T cell phenotype with high IL-4 expression (AA) or IL-13 expression (AD). RESULTS: Several gene families such as the TGF-beta family, chemokines and chemokine receptors were found to be upregulated. Matrix metalloproteinases and their inhibitors were also found to be expressed in an enhanced manner. Furthermore, factors regulating tissue turnover such as fibroblast growth factors and neurotrophic as well as vasoactive factors were found be expressed at a higher level in allergic patient compared to healthy donors. CONCLUSION: The present study reveals and confirms genes relevant for allergy and highlights an approach to applying a DNA array technique for diagnostic discrimination of allergic diseases.

The phosphatidylinositol phosphatase PTEN is under control of costimulation and regulates proliferation in human T cells.

The phosphatidylinositol phosphatase gene PTEN is a dual specific phosphatase acting on phospho amino acids but also on three phosphorylated inositol phospholipids. Present results demonstrate that PTEN is inducible by costimulatory signals in human CD4(+) T cells. PTEN expression was up-regulated on RNA and protein level in freshly isolated human CD4(+) T cells following stimulation with CD28 or CD2. In contrast, PTEN expression was high but remained CD28 and CD2 unresponsive in lymphoma cells. Intracellular staining revealed PTEN expression in CD4(+) T cell populations stimulated with anti-CD28 or anti-CD28 / anti-CD3. Stimulation with anti-CD3 alone did not induce PTEN expression. Inhibition of PTEN expression by antisense oligonucleotides in CD4(+) T cells stimulated with non-mitogenic anti-CD28 resulted in massively increased proliferation, which was sensitive to the phosphatidylinositol 3-kinase (PI3 K) inhibitor wortmannin. Although CD28 and CD2 induce PI3 K signal transduction, wortmannin did not block PTEN up-regulation by CD28 or CD2 indicating that PTEN gene expression is PI3 K independent. These results demonstrate that PTEN negatively controls costimulatory signals by antagonizing PI3 K activity in the absence of TCR engagement.