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Differential Ras signaling via the antigen receptor and IL-2 receptor in primary T lymphocytes

Reinhard E Marks1, Allen W Ho, Fabiola Rivas

  • 1Department of Pathology, Department of Medicine Section of Hematology/Oncology, The Ben May Institute for Cancer Research, University of Chicago, Chicago, IL 60637, USA.

Biochemical and Biophysical Research Communications
|December 19, 2003
PubMed

Insights

This study reveals distinct Ras signaling pathways in T cells. While IL-2 receptor engagement activates Ras and ERK, T cell receptor/CD3 ligation relies on PKC and PLC-gamma, not dominant negative Ras.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • Ras signaling is crucial in T lymphocytes but difficult to study in normal quiescent cells due to limited gene transfer technology.
  • Adenoviral transduction in T cells from transgenic mice overcomes this limitation, enabling mechanistic studies.

Purpose of the Study:

  • To investigate the distinct mechanisms of Ras activation in normal T lymphocytes upon engagement of different receptors.
  • To compare Ras signaling pathways activated by the IL-2 receptor (IL-2R) versus the T cell receptor/CD3 (TCR/CD3) complex.

Main Methods:

  • Utilized adenoviral transduction for efficient gene transfer into resting T cells from Coxsackie/adenovirus receptor transgenic mice.
  • Employed dominant-negative Ras17N (DN Ras17N) to block Ras activation.
  • Assessed Ras and ERK activation in response to IL-2R and TCR/CD3 ligation.
  • Used protein kinase C (PKC) and phospholipase C-gamma (PLC-gamma) inhibitors to probe TCR-induced signaling.

Main Results:

  • Dominant negative Ras17N blocked Ras and ERK activation upon IL-2R engagement.
  • Unexpectedly, dominant negative Ras17N did not block Ras and ERK activation upon TCR/CD3 ligation.
  • TCR/CD3-induced ERK activation was suppressed by inhibitors of PKC and PLC-gamma, suggesting alternative activation pathways.

Conclusions:

  • Demonstrates a striking contrast in Ras signaling pathways activated by IL-2R versus TCR/CD3 in normal quiescent T cells.
  • Suggests that the primary mechanism of Ras activation by TCR/CD3 in normal T cells differs from that in T-lineage tumor cell lines.

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