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 journalArticle

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
Pages (from-to)2500-2509
Number of pages10
JournalEuropean Journal of Immunology
Volume32
Issue number9
DOIs
Publication statusPublished - Sep 2002

Fingerprint

Clonal Anergy
T-Lymphocytes
Interleukin-2
CD28 Antigens
CD3 Antigens
Peripheral Tolerance
Ionomycin
MAP Kinase Signaling System
Ionophores
Autoantigens
Neoplasm Antigens
T-Cell Antigen Receptor

Keywords

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

ASJC Scopus subject areas

  • Immunology

Cite this

Constitutive active p21ras enhances primary T cell responsiveness to Ca2+ signals without interfering with the induction of clonal anergy. / Crespi, Daniela; Massa, Stefania; Basso, Veronica; Colombetti, Sara; Mueller, Daniel L.; Mondino, Anna.

In: European Journal of Immunology, Vol. 32, No. 9, 09.2002, p. 2500-2509.

Research output: Contribution to journalArticle

Crespi, Daniela ; Massa, Stefania ; Basso, Veronica ; Colombetti, Sara ; Mueller, Daniel L. ; Mondino, Anna. / Constitutive active p21ras enhances primary T cell responsiveness to Ca2+ signals without interfering with the induction of clonal anergy. In: European Journal of Immunology. 2002 ; Vol. 32, No. 9. pp. 2500-2509.
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