The precursors of CD8⁺ tissue resident memory T cells: from lymphoid organs to infected tissues

CD8⁺ tissue resident memory T cells (T_RM cells) are essential for immune defence against pathogens and malignancies, and the molecular processes that lead to T_RM cell formation are therefore of substantial biomedical interest. Prior work has demonstrated that signals present in the inflamed tissue micro-environment can promote the differentiation of memory precursor cells into mature T_RM cells, and it was therefore long assumed that T_RM cell formation adheres to a ‘local divergence’ model, in which T_RM cell lineage decisions are exclusively made within the tissue. However, a growing body of work provides evidence for a ‘systemic divergence’ model, in which circulating T cells already become preconditioned to preferentially give rise to the T_RM cell lineage, resulting in the generation of a pool of T_RM cell-poised T cells within the lymphoid compartment. Here, we review the emerging evidence that supports the existence of such a population of circulating T_RM cell progenitors, discuss current insights into their formation and highlight open questions in the field.