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Title

H-ras and N-ras are dispensable for T-cell development and activation but critical for protective Th1 immunity

AuthorsIborra, Salvador; Soto, Manuel ; Castellano, Esther; Alarcón, Balbino ; Alonso, Carlos ; Santos de Dios, Eugenio
KeywordsGuanine
Th1 response
H-ras
N-ras
Ras-deficient mice
Leishmania major
Issue Date31-Aug-2011
PublisherAmerican Society of Hematology
CitationBlood 117 (19): 5102-5111 (2011)
AbstractThe 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.
Publisher version (URL)http://dx.doi.org/10.1182/blood-2010-10-315770
URIhttp://hdl.handle.net/10261/57530
DOI10.1182/blood-2010-10-315770
ISSN0006-4971
E-ISSN1528-0020
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