Defective T cell receptor/CD3 complex signaling in human type I diabetes

Ruggero De Maria, Matilde Todaro, Giorgio Stassi, Francesco Di Blasi, Marco Giordano, Aldo Galluzzo, Carla Giordano

Research output: Contribution to journalArticle

Abstract

The autoimmune process leading to the destruction of pancreatic β-cells is mediated by T lymphocytes. Peripheral T cells from subjects with preclinical and clinical type I diabetes respond weakly in vitro to lectin stimulation. We, therefore, investigated in a group of newly diagnosed diabetic patients the presence of a defect in the signal transduction pathway of the T cell receptor (TcR)/CD3 complex. Following stimulation with anti-CD3-coupled beads, the proliferative response in diabetic T cells was significantly decreased in comparison with that from normal T cells. Interestingly, addition of either recombinant interleukin (IL)-2 or phorbol 12-myristate 13-acetate to the cell culture was able to completely restore impaired anti-CD3-induced proliferation in diabetic T cells, suggesting the presence of a defect through the TcR/CD3 pathway, located upstream of protein kinase C (PKC) activation and resulting in low IL-2 production and proliferation. Intracellular Ca2+ measurements by Fluo-3 labeling and flow cytometry analysis on diabetic and control T cells after anti-CD3 stimulation gave comparable results, indicating that this defect does not involve events leading to intracellular Ca2+ mobilization. In contrast, anti-CD3 stimulation of diabetic T cells resulted in a marked impairment of PKC translocation and CD69 antigen expression, as assessed by peptide substrate phosphorylation and by flow cytometry analysis, respectively. Taken together, our data clearly show the presence in individuals at the onset of the disease of an in vitro defect in the signal transduction pathway of the TcR/CD3 complex, resulting in ineffective PKC activation which is not able to induce normal IL-2 production and proliferation of diabetic T cells.

Original languageEnglish
Pages (from-to)999-1002
Number of pages4
JournalEuropean Journal of Immunology
Volume24
Issue number4
Publication statusPublished - Apr 1994

Keywords

  • CD3
  • Protein kinase C
  • T cell receptor
  • T lymphocytes
  • Type I diabetes

ASJC Scopus subject areas

  • Immunology

Fingerprint Dive into the research topics of 'Defective T cell receptor/CD3 complex signaling in human type I diabetes'. Together they form a unique fingerprint.

  • Cite this

    De Maria, R., Todaro, M., Stassi, G., Di Blasi, F., Giordano, M., Galluzzo, A., & Giordano, C. (1994). Defective T cell receptor/CD3 complex signaling in human type I diabetes. European Journal of Immunology, 24(4), 999-1002.