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Mice deficient for N-ras: impaired antiviral immune response and T-cell function
Ignacio Pérez de Castro1, Roberto Diaz, Marcos Malumbres
1Department of Pathology and Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, New York 10016, USA.
Abstract:
Ras proteins have a key role in the regulation of several cellular functions, and are involved in a significant percentage of human tumors. However, the specific functions of the different Ras isoforms are poorly understood. In this work, we show for the first time a specific role for N-ras in T-cell function and development. Mice defective for N-ras have low numbers of CD8 single positive thymocytes and decreased thymocyte proliferation in vitro. In Ras signaling and activation assays, KO-N-ras thymocytes showed a defective response to T-cell activation. In turn, these deficiencies resulted in a significant reduction in the production of interleukin 2 on thymocyte activation. We have also detected in vivo the functional consequences of N-ras deficiency. KO-N-ras mice showed an increased sensitivity to influenza infection, especially when low doses of virus were used. Finally, we have detected an abnormal activation pattern of downstream Ras molecules in T-cell receptor-activated KO-N-ras thymocytes that is consistent with the defective T-cell function found in these animals. All of the results derived from this work constitute a significant contribution to the knowledge of N-ras-specific functions.
Insights
This study reveals a specific role for N-ras in T-cell development and function. N-ras deficiency impairs T-cell responses, impacting immunity and potentially contributing to human tumors.
Area of Science:
- Immunology
- Molecular Biology
- Oncology
Background:
- Ras proteins regulate cellular functions and are implicated in human cancers.
- Specific functions of Ras isoforms, including N-ras, are not well understood.
- T-cell development and function are critical for immune responses.
Purpose of the Study:
- To elucidate the specific role of N-ras in T-cell function and development.
- To investigate the consequences of N-ras deficiency in T-cells.
- To understand N-ras's contribution to immune responses and disease.
Main Methods:
- Utilized knockout mice lacking N-ras (KO-N-ras).
- Assessed T-cell populations (CD8 single positive thymocytes) and proliferation in vitro.
- Performed Ras signaling and activation assays on thymocytes.
- Measured interleukin 2 production upon T-cell activation.
- Evaluated in vivo immune response to influenza infection.
Main Results:
- KO-N-ras mice exhibited reduced CD8 single positive thymocytes and impaired thymocyte proliferation.
- N-ras deficient thymocytes showed defective T-cell activation responses and reduced interleukin 2 production.
- KO-N-ras mice displayed increased sensitivity to influenza infection, particularly at low viral doses.
- Abnormal downstream Ras molecule activation patterns were observed in activated KO-N-ras thymocytes.
Conclusions:
- N-ras plays a critical and specific role in T-cell development and function.
- N-ras deficiency leads to impaired T-cell-mediated immunity and increased susceptibility to infections.
- These findings contribute significantly to understanding N-ras-specific functions in cellular processes and disease.