Transferrin-dependent crosstalk between the intestinal tract and commensal microbes contributes for immune tolerance

Crosstalks between gastrointestinal tract and commensal microbes regulate immune tolerance and maintain host intestinal homeostasis. However, molecular events that regulate the crosstalks remain poorly understood. Here, we show that microbial products (lipopolysaccharide, lipoteichoic acid and DNA) up-regulate host transferrin, an iron supplier of commensal bacteria, to induce host’s immune tolerance by negatively regulating toll-like receptor (TLR) signaling. Transferrin level in germ-free and broad-spectrum antibiotics-treated mice is much less than that in normal mice. Transferrin is found to silence TLR signaling complex by directly interacting with CD14, a co-receptor of many TLRs. Transferrin knock-down impaired host tolerogenic responses as well as broad-spectrum antibiotics treatment. Our findings reveal that commensal bacteria up-regulate and beneficially use host transferrin as a negative regulator of TLR signaling to shape host immunity and contribute for intestinal tolerance.