Constitutive active p21ras enhances primary T cell responsiveness to Ca2+ signals without interfering with the induction of clonal anergy

Daniela Crespi, Stefania Massa, Veronica Basso, Sara Colombetti, Daniel L Mueller, Anna Mondino

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Chronic engagement of the T cell receptor mediates the induction of T lymphocyte unresponsiveness called clonal anergy. The development of such unresponsiveness has been suggested as one of the mechanisms that regulate peripheral tolerance to self-antigens and hamper the capacity of tumor antigen-specific T cells to eliminate cancerous cells. In the attempt to enhance the effector function of CD4+ T lymphocytes and their resistance to clonal anergy induction, we have transduced primary T cells with a retroviral vector encoding active p21ras (RasLeu61). Here we show that RasLeu61 elicited TCR-independent activation of the Ras-Raf-ERK pathway and conferred primary T cells with the ability to secrete IL-2 in response to stimulation with a Ca2+ ionophore alone, without altering antigen-, CD3/CD28- and PMA/ionomycin-driven IL-2 secretion and T cell proliferation in vitro. However, chronic engagement of the TCR on the surface of RasLeu61 T cells still led to an inability of the cells to produce IL-2 upon restimulation. These results indicate that enforced p21ras functionality enhances primary T cells responses to calcium-generated signals, but is insufficient to prevent TCR-driven T cell unresponsiveness and suggest that additional biochemical mechanisms, independent of p21ras, negatively regulate IL-2 production in unresponsive T cells.

Original languageEnglish (US)
Pages (from-to)2500-2509
Number of pages10
JournalEuropean Journal of Immunology
Volume32
Issue number9
DOIs
StatePublished - Sep 1 2002

Keywords

  • Anergy
  • Gene therapy
  • Signal transduction
  • Suppression
  • T lymphocyte
  • Tolerance

Fingerprint Dive into the research topics of 'Constitutive active p21<sup>ras</sup> enhances primary T cell responsiveness to Ca<sup>2+</sup> signals without interfering with the induction of clonal anergy'. Together they form a unique fingerprint.

Cite this