title: H-ras and N-ras are dispensable for T-cell development and activation but critical for protective Th1 immunity.
abstract: The small guanine nucleotide binding proteins of the Ras family, including in mammals the highly homologous H-ras, N-ras, and K-ras isoforms, are rapidly activated on ligation of the T-cell antigen receptor (TCR), but whether each isoform plays specific roles in T cells is largely unknown. Here, we show, with the use of mice specifically lacking H-ras or N-ras, that these isoforms are dispensable for thymocyte development and mature T-cell activation. By contrast, CD4⁺ T cells from Ras-deficient mice exhibited markedly decreased production of the Th1 signature cytokine IFN-γ early after TCR stimulation, concomitantly with impaired induction of the Th1-specific transcription factor T-bet. Accordingly, Ras-deficient mice failed to mount a protective Th1 response in vivo against the intracellular parasite Leishmania major, although they could be rendered resistant to infection if a Th1-biased milieu was provided during parasite challenge. Collectively, our data indicate that the TCR recruits distinct Ras isoforms for signal transduction in developing and mature T cells, thus providing a mechanism for differential signaling from the same surface receptor. Furthermore, we demonstrate for the first time that H-ras and N-ras act as critical controllers of Th1 responses, mostly by transmitting TCR signals for Th1 priming of CD4⁺ T cells.
authors: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Departamento de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain.
authors: Salvador
authors: S
authors: Iborra
authors: Manuel
authors: M
authors: Soto
authors: Luiz
authors: L
authors: Stark-Aroeira
authors: Esther
authors: E
authors: Castellano
authors: Balbino
authors: B
authors: Alarcón
authors: Carlos
authors: C
authors: Alonso
authors: Eugenio
authors: E
authors: Santos
authors: Edgar
authors: E
authors: Fernández-Malavé
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology; D002469:Cell Separation; D005434:Flow Cytometry; D011905:Genes, ras / Q000276:immunology*; D015151:Immunoblotting; D007896:Leishmaniasis / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*
chemical_list: D011948:Receptors, Antigen, T-Cell