Role of Ras isoforms in γδ T-cell development
Journal of Translational Medicine volume 10, Article number: O6 (2012)
The small guanine nucleotide binding proteins of the Ras family (H-, K-, and N-ras isoforms) couple surface receptors, including T-cell antigen receptors, to a variety of cellular responses. Ras proteins are highly homologous and expressed ubiquitously, raising questions as to their functional specificity. H-ras and N-ras have been shown to be dispensable for development in the thymus but critical for peripheral Th1 differentiation of αβ T cells . In the γδ T-cell lineage, in contrast, the specific function of Ras isoforms had not been addressed.
We aimed at identifying the specific roles of H-ras and N-ras in γδ T-cell development, particularly, in the generation of γδ T-cell subsets defined by expression of CD27.
Mice and methods
Mice deficient for H-ras or N-ras were analyzed by multi-parametric flow cytometry. In addition, N-ras-deficient mice with impaired αβ T-cell development were generated by breeding with CD3δ KO mice and analyzed.
Ras isoform-deficient mice exhibited normal frequencies and numbers of γδ T cells in the thymus, which expressed normal levels of surface γδTCR, but a consistent decrease of CD27+ γδ T cells in peripheral lymphoid organs, compared to controls. Conversely, in mice lacking mature αβ T cells, N-ras deficiency resulted in reduced numbers of CD27+ γδ T cells, with concomitant increase of the CD27- population, in the thymus but not in the periphery. This suggests that signals from αβ T-cell thymocytes for developing CD27+ γδ T cells are partly N-ras-dependent.
As previously shown for αβ T cells, H-ras and N-ras are dispensable for intrathymic development of γδ T cells, but they could be involved in finely regulating survival and/or expansion of γδ T cells in the periphery, in agreement with recent findings in mice lacking RasGRP1 , a guanine nucleotide exchange factor for Ras.
The study was supported by grant FIS PI11/02198 from Instituto de Salud Carlos III to EF-M.
Iborra S, Soto M, Stark-Aroeira L, Castellano E, Alarcón B, Alonso C, Santos E, Fernández-Malavé E: H-ras and N-ras are dispensable for T-cell development and activation but critical for protective Th1 immunity. Blood. 2011, 117: 5102-5111. 10.1182/blood-2010-10-315770.
Chen Y, Ci X, Gorentla B, Sullivan SA, Stone JC, Zhang W, Pereira P, Lu J, Zhong XP: Differential requirement of RasGRP1 for γδ T cell development and activation. J Immunol. 2012, 189: 61-71. 10.4049/jimmunol.1103272.
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Marín-Marín, A.V., Pérez, E.J., Santos, E. et al. Role of Ras isoforms in γδ T-cell development. J Transl Med 10 (Suppl 3), O6 (2012). https://doi.org/10.1186/1479-5876-10-S3-O6