Beyond pathogen recognition: C-type lectin receptors in microbiota regulation

A central challenge faced by the immune system is not simply detecting microbes but determining how to respond to them. In the intestine, where commensals and pathogens coexist, this decision is neither binary nor dictated by a single receptor. Instead, it emerges from the integration of signals across multiple pattern recognition receptors (PRRs), which together encode microbial identity and context. Among these, C-type lectin receptors (CLRs) occupy a unique position. By recognizing diverse ligands present on bacteria, fungi, viruses, and even host derived molecules, CLRs extend microbial sensing beyond pathogen detection to include signals of tissue state and environmental context. In doing so, CLRs function not merely as detectors of specific microbes, but as regulators that calibrate immune responses across the spectrum of tolerance and defense. Many reviews exist that detail how CLRs regulate pathogen defense, so here we will focus on the recent literature that demonstrates how these molecules influence maintenance of homeostasis with our commensal microbiota.