Tumor necrosis factor receptor superfamily member 5 and Low-density lipoprotein receptor-related protein 1 complex (CD40/CD91)

The CD40/CD91 receptor complex is a functional co-receptor system primarily expressed on the surface of professional antigen-presenting cells (APCs), such as dendritic cells and macrophages. It consists of CD40 (Tumor Necrosis Factor Receptor Superfamily Member 5) and CD91 (Low-Density Lipoprotein Receptor-Related Protein 1), which work in tandem to recognize and internalize extracellular heat shock proteins (HSPs), such as HSP70 and gp96. This interaction is critical for the uptake of HSP-chaperoned antigenic peptides, which are then processed and cross-presented on MHC class I molecules to initiate a potent CD8+ T-cell response. Beyond its role in adaptive immunity, the complex mediates innate immune signaling, leading to the production of pro-inflammatory cytokines like IL-12 and TNF-alpha. In oncology, this pathway is exploited by HSP-based vaccines (e.g., Vitespen) and peptide vaccines (e.g., GV1001) to enhance anti-tumor immunity. Additionally, CD40 itself is a major therapeutic target for agonistic antibodies in cancer and antagonistic antibodies in autoimmune diseases, where its interaction with CD91 may influence the overall signaling outcome and therapeutic efficacy.

Other names

CD40-CD91 complexHSP70 receptor complexgp96 receptor complexLRP1/TNFRSF5 complexHeat shock protein receptor complex

Agonism of CD40 to activate antigen-presenting cells; Antagonism of CD40 to inhibit costimulatory signaling; Receptor-mediated endocytosis of heat shock protein-peptide complexes for antigen cross-presentation.