Trained to respond: Signal-level modifications of endosomal TLRs

Cells can modify their future behavior based on prior exposures, a phenomenon known as cellular adaptation. In innate immunity, such adaptive responses are critical for fine-tuning host defense, enabling trained immunity or tolerance. These states have been largely attributed to long-lasting epigenetic or metabolic reprogramming. Whether prior microbial encounters can rapidly lower receptor signaling thresholds to selectively enhance responsiveness of individual innate immune receptors remains unknown.Here, we identify a previously unrecognized, non-genetic form of cellular adaptation. We show that TLR4 activation by LPS, while inducing classical endotoxin tolerance, simultaneously primes macrophages for enhanced responses to subsequent activation of the RNA sensor TLR7. Because TLR4 and TLR7 use the same signaling machinery, this indicates that they are selectively reprogrammed in this process. TLR7 training requires type I interferons and is marked by a strong increase in Myddosome assemblies at endosomal membranes, without changes in TLR7 abundance or ligand uptake. These findings reveal that innate immune training can be rapidly encoded at the level of receptor-proximal signaling, linking microbial priming to enhanced nucleic acid immunity and potentially to TLR7-driven autoimmunity in genetically predisposed individuals.