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B-Myb Overexpression Results in Activation and Increased Fas/Fas Ligand-Mediated Cytotoxicity of T and NK Cells¹

Mark A. Powzaniuk^*, Rossana Trotta^*, Matthew J. Loza^*, Amy Harth^*, Renato V. Iozzo, Lawrence C. Eisenlohr^*, Bice Perussia^* and Bruno Calabretta^2,*

^* Department of Microbiology and Immunology, Kimmel Cancer Center, and Department of Pathology and Cell Biology, Jefferson Medical College, Philadelphia, PA 19107

The human B-myb gene encodes a transcriptional regulator that plays an important role in cell cycle progression, differentiation, and survival. To assess the in vivo role of B-myb, we investigated the phenotype of mouse transgenic lines in which B-Myb expression in lymphoid tissues was driven by the LCK proximal promoter. Overexpression of B-Myb had no measurable effect on the subsets of splenic and thymic lymphocytes, but was associated with increased expression of Fas ligand in NK and T cells. B-Myb-overexpressing splenocytes expressed higher IFN- levels and contained higher percentages of cytokine-producing cells than wild-type (wt) splenocytes, as detected by Western blot analysis and ELISPOT assays, respectively. Ex vivo-cultured transgenic thymocytes and splenocytes had decreased survival compared with the corresponding cells from wt mice, possibly dependent on increased expression of Fas ligand. In addition, Fas ligand-dependent cytotoxicity of transgenic T and NK cells was significantly higher than that mediated by their wt counterparts. Together, these results indicate that B-Myb overexpression results in T and NK cell activation and increased cytotoxicity. Therefore, in addition to its well-established role in proliferation and differentiation, B-myb also appears to be involved in activation of NK and T cells and in their regulation of Fas/Fas ligand-mediated cytotoxicity