Tissue-resident memory CD8⁺ T cells shape local and systemic secondary T cell responses

Tissue-resident memory CD8⁺ T cells (T_RM cells) are crucial in protecting against reinvading pathogens, but the impact of reinfection on their tissue confinement and contribution to recall responses is unclear. We developed a unique lineage tracer mouse model exploiting the T_RM-defining transcription factor homolog of Blimp-1 in T cells (Hobit) to fate map the T_RM progeny in secondary responses. After reinfection, a sizeable fraction of secondary memory T cells in the circulation developed downstream of T_RM cells. These tissue-experienced ex-T_RM cells shared phenotypic properties with the effector memory T cell population but were transcriptionally and functionally distinct from other secondary effector memory T cell cells. Adoptive transfer experiments of T_RM cells corroborated their potential to form circulating effector and memory cells during recall responses. Moreover, specific ablation of primary T_RM cell populations substantially impaired the secondary T cell response, both locally and systemically. Thus, T_RM cells retain developmental plasticity and shape both local and systemic T cell responses on reinfection.