Prolonged but finite antigen presentation promotes reversible defects of “helpless” memory CD8⁺ T cells

Generation of functional memory CD8⁺ T cells typically requires engagement of CD4⁺ T cells. In certain acutely resolving infections, however, effector and memory CD8⁺ T (Tmem) cell formation appears impervious to the lack of CD4⁺ T cell help. Nevertheless, “helpless” CD8⁺ Tmem cells may respond poorly upon rechallenge. The origin and long-term fate of helpless CD8⁺ Tmem cells remain incompletely understood. Using multiple host-pathogen systems, we demonstrate that helpless effector CD8⁺ T cell differentiation was largely normal, with a paradoxical accumulation of TCF1^hi “memory precursors.” However, exposure of CD8⁺ T cells to residual antigen impaired the development of the Tmem pool. These defects eventually resolved over time, with full restoration of memory potential and recall capacity. Our findings identify prolonged antigen presentation under helpless conditions as an essential determinant for transient CD8⁺ Tmem cell dysfunction in acutely resolving infections and highlight plasticity within the Tmem compartment, with implications for vaccination strategies and beyond.