Kupffer cells are key mediators of antigen-specific immune tolerance by peptide-coupled red blood cells

Coupling red blood cells (RBC) with a cocktail of MS immunodominant peptides is a promising approach to induce antigen-specific immune tolerance in patients. Here, we show that RBC coupled with disease-inducing antigen efficiently prevent the development of experimental autoimmune encephalomyelitis, when administered prophylactically, and ameliorate disease symptoms when given therapeutically.

The tolerogenic activity of peptide-coupled RBC (pcRBC) was antigen-specific and dependent on both cell and peptide dose. Kupffer cells (KC) were the primary phagocytes of pcRBC, and their uptake of pcRBC did not require C3, SIRPα, and Stabilin 1 and 2. Most importantly, KC were indispensable for the induction of tolerance, which was accompanied by PD-L1 upregulation and a tolerogenic transcriptional shift.