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. Van Gisbergen and colleagues show that tissue-resident memory T cells, genetically marked in Hobit reporter mice, can exit tissues upon reinfection and contribute to systemic memory responses.