The rationale for the IL-2-independent generation of the self-renewing central memory CD8+ T cells

Clones of CD8(+) T cells that have been selected in the primary response must have a mechanism by which they can continuously or intermittently generate new effector cells. Several years ago, this mechanism was proposed to involve a self-renewing, stem cell-like subset that could avoid the differentiating effects of interleukin-2 (IL-2). The model considered the stem cell subset to be contained within the central memory population of CD8(+) T cells (T-CM). This proposal was inconsistent with subsequent findings suggesting that all antigen-activated CD8(+) T cells differentiated to effector cells (T-EFF) during the primary response and that T-CM developed during the memory phase by de-differentiating from effector memory cells (T-EM). However, findings have since been reported that support the stem cell model. First, studies indicate that T-EM do not serve as the precursors of T-CM. Second, transcriptional repressors of IL-2 signaling do enhance the memory response. Third, memory cells lacking effector functions and with a capacity to replicate in a secondary response develop in the absence of signaling through the IL-2/IL-15 receptor. Taken together, these findings suggest that antigen-activated CD8(+) T cells with a stem cell-like capability for maintaining proliferative potential develop by an unknown IL-2-independent process. The challenge is now to identify this unknown pathway of clonal expansion.