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

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.This work was supported by Instituto de Salud Carlos III (grant FIS PI080102; E.F.-M.), Comunidad de Madrid (CAM; grant GR/SAL/0168/2004; E.F.-M.), and Universidad Complutense-CAM (grant CCG08-UCM/SAL-4215; E.F.-M.) and by Instituto de Salud Carlos III (grants FIS PI021570 and RTICC-RD06/0020/000; E.S.) and Junta de Castilla y León (grants SA044A08 and GR93; E.S.). S.I. was supported by the “Sara Borrell” Program of FIS-ISCIII.Peer reviewe