Early Signals during CD8+ T Cell Priming Regulate the Generation of Central Memory Cells

The CD8(+) T cell response to infection is characterized by the appearance of short-lived (CD127(low) killer cell lectin-like receptor G 1-high) and memory-precursor (CD127(high) killer cell lectin-like receptor G 1-low) effector cells. How and when central-memory T (T(CM); CD62L(high) CCR7(+)) cell and effector-memory T(T(EM); CD62L(low) CCR7(-)) cell subsets are established remains unclear. We now show that the T(CM) cell lineage represents an early developmental branchpoint during the CD8(+) T cell response to infection. Central-memory CD8(+) T cells could be identified prior to the peak of the CD8(+) T cell response and were enriched in lymphoid organs. Moreover, the kinetics and magnitude of T(CM) cell development were dependent on the infectious agent. Furthermore, the extent of early Ag availability, which regulated programmed death-1 and CD25 expression levels, controlled the T(CM)/T(EM) cell lineage decision ultimately through IL-2 and IL-15 signaling levels. These observations identify key early signals that help establish the T(CM)/T(EM) cell dichotomy and provide the means to manipulate memory lineage choices.