Linking diacylglycerol kinase to T cell anergy.

Nature Immunology (Impact Factor: 24.97). 12/2006; 7(11):1132-4. DOI: 10.1038/ni1106-1132
Source: PubMed
  • The Epigenetics of Autoimmune Diseases, 04/2009: pages 75 - 94; , ISBN: 9780470743553
  • [Show abstract] [Hide abstract]
    ABSTRACT: Monomorphic MHC class II determinants are attractive targets for immunomodulation. HLA-DR ligation on antigen-presenting cells (APCs) can dramatically alter their function or induce cell death. In monocytes, HLA-DR triggering diminishes their capacity to stimulate T cell proliferation. To further investigate this monocyte-dependent T cell inhibition, we activated human T cells +/- HLA-DR triggering on APCs and tested whether this can induce T cell anergy. Only anti-HLA-DR, but not anti-proliferative control agent anti-CD45, could modulate monocytes in primary cultures with stimulated T cells, so that T cells were hyporesponsive during re-stimulation. Cell separation studies demonstrated that HLA-DR ligation on monocytes is sufficient for mediating T cell anergy. Secretion of monokines was severely reduced after primary culture. Monocytes anergized independently of soluble factors. Extracellular signal-regulated kinase (ERK) phosphorylation occurred early with anti-HLA-DR, but late with anti-CD45 antibody. However, ERK inhibition did not reverse the T cell-anergizing potential of HLA-DR-ligated monocytes implicating other signaling pathways involved in tolerance induction. When analyzing the anergized T cells, they were refractory to exogenous IL-2 and characterized by defective secretion of various cytokines. Expression of CD25, CD28, intracellular CD3zeta and CTLA-4 was reduced. The hyporesponsive T cells up-regulated cell-cycle inhibitors p27(kip1) and p21(cip1) in correlation with human T cell anergy. In contrast, caspase-3 and -8, known to contribute to T cell proliferation, were equally decreased in anti-HLA-DR- and anti-CD45-inhibited cultures. In summary, anti-HLA-DR treatment can generate tolerogenic monocytes transmitting T cell anergy that may be exploited for future immunomodulatory strategies to treat immune-mediated disease states.
    International Immunology 05/2008; 20(4):601-13. DOI:10.1093/intimm/dxn019 · 3.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Induction of T cell immune tolerance is thought to be a good method for treatment of asthma. Diacylglycerol kinases alpha (DGKα), enzymes that catalyze phosphorylation of diacylglycerol to produce phosphatidic acid, could inhibit diacylglycerol (DAG)-mediated signaling following T-cell receptor engagement and prevent T cell hyperactivation, thus playing important roles in the induction of T cell anergy. In the present study, we aimed to investigate the effects of DNA vaccine encoding DGKα gene administration on allergen-induced airway allergic inflammation in the murine model of asthma. Animal models were created and plasmid containing DGKα were constructed. Cytokine production was detected after the administration of DGKα gene plasmid. Immunization of mice with alum-adsorbed ovalbumin (OVA) followed by challenged with inhalation of aerosolized OVA resulted in the development of airway allergic inflammation. Administration of DGKα gene before the aerosolized OVA challenge significantly decreased the allergic airway inflammation and eosinophil infiltration in bronchoalveolar lavage fluid (BALF). Immunization with DGKα DNA vaccine decreased OVA-specific IgE and interleukin 13 (IL-13) levels in sera, and increased the IFN-γ level in BALF. The results of the present study provide evidence for the potential utility of the administration of DGKα DNA vaccine as an approach to gene therapy for asthma.
    International journal of clinical and experimental pathology 01/2013; 6(11):2404-11. · 1.78 Impact Factor


1 Download
Available from