Pro-apoptotic Bim regulates NK cell contraction and the generation of the NK memory pool following viral infection (P6106)

Abstract

Abstract Apoptosis is critical in lymphocyte development and homeostasis; moreover, this pathway eliminates activated lymphocytes and prevents immune pathology during viral infection. Pro-apoptotic factor Bim controls LCMV-specific T cell contraction and the formation of memory T cells. Natural killer (NK) cells also undergo antigen-driven expansion to become long-lived memory cells after mouse cytomegalovirus (MCMV) infection. Bim expression is decreased in memory NK cells; therefore, we examined the role of Bim in regulating the MCMV-driven memory NK pool. Ly49H+ Bim-/- NK cells respond similarly to wild-type cells early after MCMV. However, following the m157-driven expansion phase, Bim-/- Ly49H+ NK cells show impaired contraction and significantly outnumber wild-type cells by day 14. Importantly, the inability to reduce the Ly49H+ effector pool leads to a larger Bim-/- NK memory subset; these Bim-/- memory cells display a less mature phenotype (CD11blo,CD27hi) and lower levels of NK memory markers, KLRG1 & Ly6c. Furthermore, compared to wild-type memory NK cells, Bim-/- cells are functionally impaired in response to receptor-mediated stimulation, despite equal responses in naïve cells. These results suggest that apoptosis of antigen-specific effector NK cells is critical in generating a potent memory pool. Further studies are required to elucidate the mechanisms that drive apoptosis in most activated NK cells, but spare a small subset to become long-lived memory cells.