IFN-γ Regulates CD8+ Memory T Cell Differentiation and Survival in Response to Weak, but Not Strong, TCR Signals

In response to primary Ag contact, naive mouse CD8(+) T cells undergo clonal expansion and differentiate into effector T cells. After pathogen clearance, most effector T cells die, and only a small number of memory T cell precursors (T-MPs) survive to form a pool of long-lived memory T cells (T-Ms). Although high-and low-affinity CD8(+) T cell clones are recruited into the primary response, the T-M pool consists mainly of high-affinity clones. It remains unclear whether the more efficient expansion of high-affinity clones and/or cell-intrinsic processes exclude low-affinity T cells from the T-M pool. In this article, we show that the lack of IFN-gamma R signaling in CD8(+) T cells promotes T-M formation in response to weak, but not strong, TCR agonists. The IFN-gamma-sensitive accumulation of T-Ms correlates with reduced mammalian target of rapamycin activation and the accumulation of long-lived CD62L(hi)Bcl-2(hi) Eomes(hi) T-MPs. Reconstitution of mammalian target of rapamycin or IFN-gamma R signaling is sufficient to block this process. Hence, our data suggest that IFN-gamma R signaling actively blocks the formation of T-MPs responding to weak TCR agonists, thereby promoting the accumulation of high-affinity T cells finally dominating the T-M pool.