Abstract
Generation of functional CD8 (+) T cell memory typically requires engagement of CD4 (+) T cells. However, in certain scenarios, such as acutely-resolving viral infections, effector (T (E) ) and subsequent memory (T (M) ) CD8 (+) T cell formation appear impervious to a lack of CD4 (+) T cell help during priming. Nonetheless, such "helpless" CD8 (+) T (M) respond poorly to pathogen rechallenge. At present, the origin and long-term evolution of helpless CD8 (+) T cell memory remain incompletely understood. Here, we demonstrate that helpless CD8 (+) T (E) differentiation is largely normal but a multiplicity of helpless CD8 T (M) defects, consistent with impaired memory maturation, emerge as a consequence of prolonged yet finite exposure to cognate antigen. Importantly, these defects resolve over time leading to full restoration of CD8 (+) T (M) potential and recall capacity. Our findings provide a unified explanation for helpless CD8 (+) T cell memory and emphasize an unexpected CD8 (+) T (M) plasticity with implications for vaccination strategies and beyond.