Mice deficient for N-ras: impaired antiviral immune response and T-cell function.
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.
Pérez de Castro
Ignacio
I
Department of Pathology and Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, New York 10016, USA.
Diaz
Roberto
R
Malumbres
Marcos
M
Hernández
María-Inmaculada
MI
Jagirdar
Jaishree
J
Jiménez
María
M
Ahn
Daniel
D
Pellicer
Angel
A
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D011905:Genes, ras / Q000276:immunology*; D009980:Influenza A virus / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018631:ras Proteins / Q000172:deficiency* / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D020033:Protein Isoforms; D018631:ras Proteins