Formation of IL-7Rαhigh and IL-7Rαlow CD8 T Cells during Infection Is Regulated by the Opposing Functions of GABPα and Gfi-1

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Abstract
IL-7 is essential for the survival of naive and memory T cells, and IL-7 receptor α-chain (IL-7Rα) expression is dynamically regulated in activated CD8 T cells during acute viral and bacterial infections. Most virus-specific CD8 T cells become IL-7Rαlow and are relatively short-lived, but some escape IL-7Rα repression (referred to as IL-7Rαhigh memory precursor effector cells) and preferentially enter the memory CD8 T cell pool. How antiviral effector CD8 T cells regulate IL-7Rα expression in an “on and off” fashion remains to be characterized. During lymphocytic choriomeningitis virus infection, we found that opposing actions of the transcription factors GABPα (GA binding protein α) and Gfi-1 (growth factor independence 1) control IL-7Rα expression in effector CD8 T cells. Specifically, GABPα was required for IL-7Rα expression in memory precursor effector cells, and this correlated with hyperacetylation of the Il7ra promoter. In contrast, Gfi-1 was required for stable IL-7Rα repression in effector CD8 T cells and acted by antagonizing GABPα binding and recruiting histone deacetylase 1, which deacetylated the Il7ra promoter. Thus, Il7ra promoter acetylation and activity was dependent on the reciprocal binding of GABPα and Gfi-1, and these data provide a biochemical mechanism for the generation of stable IL-7Rαhigh and IL-7Rαlow states in virus-specific effector CD8 T cells.