An Early Burst of Cytokine Production Before the First Cell Division Influences CD8 T Cell Differentiation

The differentiation of CD8 T cells into effector and memory populations is guided by a combination of antigenic, costimulatory, and cytokine signals. Here we show that within 24 hours of activation naïve CD8 T cells undergo a rapid, dynamic, and heterogeneous burst of IL-2 and IFN-γ synthesis. This divergent early response develops with every CD8 T cell specificity analyzed, manifests in vivo and in vitro, and occurs prior to the first cell division. Nevertheless, how the intrinsic manufacture of distinct cytokines forecasts and influences the properties and fates of the producer cell itself are not well defined. We demonstrate that the initial cell intrinsic synthesis of IL-2 attenuates IL-2-dependent STAT5 signaling, but that this is not due to differences in the surface expression of the IL-2 receptor complex. These functionally discrete subsets are transcriptionally distinct and begin to display differences in the expression of hallmark effector and memory associated genes. Using cytokine reporter systems, we reveal that these early functional differences are consequential for establishing fate biases and directing the gain of effector and memory T cell properties. The bifurcation between the abilities of IL-2-producing and non-producing subsets to elaborate STAT5 signaling are consistent with a model in which non-IL-2-producing CD8 T cells are more receptive to extrinsic IL-2 signals. This enables a more terminally differentiated series of effector CD8 T cells that are licensed by cytokine signals to rapidly form. However, both IL-2-producing and non-producing CD8 T cells are capable of acquiring memory traits.