Functional impairment of “helpless” CD8+memory T cells is transient and driven by prolonged but finite cognate antigen presentation

Abstract

SUMMARYGeneration of functional CD8+T cell memory typically requires engagement of CD4+T cells. However, in certain scenarios, such as acutely-resolving viral infections, effector (TE) and subsequent memory (TM) CD8+T cell formation appear impervious to a lack of CD4+T cell help during priming. Nonetheless, such “helpless” CD8+TMrespond 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+TEdifferentiation is largely normal but a multiplicity of helpless CD8 TMdefects, 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+TMpotential and recall capacity. Our findings provide a unified explanation for helpless CD8+T cell memory and emphasize an unexpected CD8+TMplasticity with implications for vaccination strategies and beyond.