Innate immune memory in mucosa: where is it encoded?

Trained immunity describes the capacity of innate immune cells to develop memory-like responses following a prior challenge. Early studies focused on myeloid cells and bone marrow progenitors. Extension of this concept to mucosal tissues, however, presents a more complex picture. These barrier sites harbor diverse, long-lived immune populations that interact with structural cells and neuronal circuits to actively shape immune responses. Emerging evidence suggests that memory-like programs extend beyond immune cells to include epithelial, stromal, and neuronal compartments. We propose that trained immunity in mucosal surfaces is distributed across the tissue ecosystem, encompassing progenitors, tissue-resident populations, and the tissue niche. This expanded framework redefines innate immune memory and has important implications for infections and chronic inflammatory diseases.