Impact of multiple hits with cognate antigen on memory CD8+ T-cell fate

Antigen-driven activation of CD8+ T cells results in the development of a robust anti-pathogen response and ultimately leads to the establishment of long-lived memory T cells. During the primary response, CD8+ T cells interact multiple times with cognate antigen on distinct types of antigen-presenting cells. The timing, location and context of these antigen encounters significantly impact the differentiation programs initiated in the cells. Moderate re-activation in the periphery promotes the establishment of the tissue-resident memory T cells that serve as sentinels at the portal of pathogen entry. Under some circumstances, moderate re-activation of T cells in the periphery can result in the excessive expansion and accumulation of circulatory memory T cells, a process called memory inflation. In contrast, excessive re-activation stimuli generally impede conventional T-cell differentiation programs and can result in T-cell exhaustion. However, these conditions can also elicit a small population of exhausted T cells with a memory-like signature and self-renewal capability that are capable of responding to immunotherapy, and restoration of functional activity. Although it is clear that antigen re-encounter during the primary immune response has a significant impact on memory T-cell development, we still do not understand the molecular details that drive these fate decisions. Here, we review our understanding of how antigen encounters and re-activation events impact the array of memory CD8+ T-cell subsets subsequently generated. Identification of the molecular programs that drive memory T-cell generation will advance the development of new vaccine strategies that elicit high-quality CD8+ T-cell memory.