INVOLVEMENT OF P21(RAS) DISTINGUISHES POSITIVE AND NEGATIVE SELECTION IN THYMOCYTES

Small molecular weight GTP binding proteins of the ras family have been implicated in signal transduction from the T cell antigen receptor (TCR), To test the importance of p21(ras) in the control of thymocyte development, we generated mice expressing a dominant-negative p21(ras) protein (H-rasN17) in T lineage cells under the control of the lck proximal promoter, Proliferation of thymocytes from lck-H-rasN17 mice in response to TCR stimulation was nearly completely blocked, confirming the importance of p21(ras) in mediating TCR-derived signals in mature CD4(+)8(-) or CD8(+)4(-) thymocytes. In contrast, some TCR-derived signals proceeded unimpaired in the CD4(+)8(+) thymocytes of mice expressing dominant-negative p21(ras). Analysis of thymocyte development in mice made doubly transgenic for the H-Y-specific TCR and lck-H-rasN17 demonstrated that antigen-specific negative selection occurs normally in the presence of p21(H-rasN17). Superantigen-induced negative selection in vivo also proceeded unhindered in H-rasN17 thymocytes, In contrast, positive selection of thymocytes in the H-Y mice was severely compromised by the presence of p21(H-rasN17). These observations demonstrate that positive and negative selection, two conceptually antithetical consequences of TCR stimulation, are biochemically distinguishable.