Functional impairment of "helpless" CD8 ⁺ memory T cells is transient and driven by prolonged but finite cognate...

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.