Cytosolic Recognition of RNA Drives the Immune Response to Heterologous Erythrocytes

The archetypal T cell-dependent antigen is sheep red blood cells (SRBCs), which have defined much of what we know about humoral immunity. Early studies using solubilized or sonicated SRBCs argued that the intact structure of SRBCs was important for optimal antibody responses. However, the reason for the requirement of intact SRBCs for the response to polyvalent protein antigen remained unknown. Here, we report that the immune response to SRBCs is driven by cytosolic recognition of SRBC RNA through the RIG-I-like receptor (RLR)-mitochondrial anti-viral signaling adaptor (MAVS) pathway. Following the uptake of SRBCs by antigen-presenting cells, the MAVS signaling complex governs the differentiation of both T follicular cells and antibody-producing B cells. Importantly, the involvement of the RLR-MAVS pathway precedes that of endosomal Toll-like receptor pathways, yet both are required for optimal effect. Immunization with sheep red blood cells (SRBCs) has been used for almost a century to study antibody generation. Loetsch et al. now show that, after engulfment, SRBC RNA accesses antigen-presenting cell RNA-sensing pathways to stimulate the immune system.