Abstract During viral or bacterial infection, the distinct effects of inflammation and antigenic stimulation on effector and memory cell differentiation in CD8 T cells remain to be better defined. Our recent findings show that two subsets of effector CD8 T cells that have distinct cell fates are formed during acute infection -- the KLRG1hi IL-7Rlo short-lived effector cells (SLECs) and the KLRG1lo IL-7Rhi memory precursor cells (MPCs). SLECs will undergo apoptosis after infection subsides whereas MPCs survive and become memory CD8 T cells. Here we show that inflammation plays an important role in generating SLECs during infection. Specifically, we found that priming CD8 T cells in the absence of overt inflammation using peptide-coated dendritic cells (DCs) induced primarily MPCs, but SLECs did not form. However, if CD8 T cell activation occurred in the presence of CpG then SLECs formed, and this was TLR9-dependent. In addition, the two signals (antigen + inflammation) needed to act in concert to induce formation of the SLECs. Next, we found that IL-12 alone, but not IFNγ, was sufficient to induce SLECs. However, IFNγ appears to be permissive in this process since IFN γR−/− CD8 T cells failed to form SLECs with peptide-coated DCs + CpG. Together, these results provide new insight into how inflammatory signals control effector cell differentiation and longevity and thus, provides a novel link between inflammation and T cell homeostasis.