H-ras and N-ras are dispensable for T-cell development and activation but critical for protective Th1 immunity
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- Salvador Iborra
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Departamento de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain;
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- Manuel Soto
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Departamento de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain;
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- Luiz Stark-Aroeira
- Unidad de Investigación, Hospital Universitario de La Paz, Madrid, Spain;
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- Esther Castellano
- Centro de Investigación del Cáncer, IBMCC, CSIC-USAL, Universidad de Salamanca, Salamanca, Spain; and
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- Balbino Alarcón
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Departamento de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain;
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- Carlos Alonso
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Departamento de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain;
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- Eugenio Santos
- Centro de Investigación del Cáncer, IBMCC, CSIC-USAL, Universidad de Salamanca, Salamanca, Spain; and
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- Edgar Fernández-Malavé
- Inmunología, Facultad de Medicina, Universidad Complutense, Madrid, Spain
書誌事項
- 公開日
- 2011-05-12
- DOI
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- 10.1182/blood-2010-10-315770
- 公開者
- American Society of Hematology
この論文をさがす
説明
<jats:title>Abstract</jats:title><jats:p>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.</jats:p>
収録刊行物
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- Blood
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Blood 117 (19), 5102-5111, 2011-05-12
American Society of Hematology
