Trends Immunol. 2026 May 16:S1471-4906(26)00101-8. doi: 10.1016/j.it.2026.04.008. Online ahead of print.
ABSTRACT
The adaptive immune system (AIS) is traditionally viewed as a defensive vertebrate innovation forged by pathogen pressure. Yet many of its core features suggest it is a homeostatic, regulatory circuit, not simply a sophisticated means of antimicrobial warfare. The horizontal transfer of mitochondria–endogenous endosymbiotic organelles-is a conserved mechanism for maintaining tissue homeostasis through metabolic rescue but can alter a cell’s identity and provoke immune responses. We propose that escalating multicellular complexity accommodated mitochondrial mobility-and the inevitable intrinsic immunological danger it presents-through a complementary supervisory system with buffering (tolerance), contextualization (specificity), memory, and eliminatory capacities. This perspective reframes the AIS as a constitutive danger management network, integrating tissue homeostasis, metabolic surveillance, immune tolerance, and immunological defense.
PMID:42142972 | DOI:10.1016/j.it.2026.04.008