CD97 promotes spleen dendritic cell homeostasis through the mechanosensing of red blood cells

Dendritic cells (DCs) are crucial for initiating adaptive immune responses. However, the factors that control DC positioning and homeostasis are incompletely understood. We found that type-2 conventional DCs (cDC2s) in the spleen depend on G alpha(13) and adhesion G protein-coupled receptor family member-E5 (Adgre5, or CD97) for positioning in blood-exposed locations. CD97 function required its autoproteolytic cleavage. CD55 is a CD97 ligand, and cDC2 interaction with CD55-expressing red blood cells (RBCs) under shear stress conditions caused extraction of the regulatory CD97 N-terminal fragment. Deficiency in CD55-CD97 signaling led to loss of splenic cDC2s into the circulation and defective lymphocyte responses to blood-borne antigens. Thus, CD97 mechanosensing of RBCs establishes a migration and gene expression program that optimizes the antigen capture and presentation functions of splenic cDC2s.

Automated summary

Dendritic cells (DCs) are crucial for initiating adaptive immune responses. The positioning and homeostasis of DCs are controlled by factors that are not fully understood. This study found that type-2 conventional DCs (cDC2s) in the spleen rely on G alpha(13) and CD97 for positioning in blood-exposed locations. CD97 function requires its autoproteolytic cleavage. Interaction between cDC2s and red blood cells (RBCs) expressing CD55 under shear stress conditions causes extraction of the regulatory CD97 N-terminal fragment. Loss of CD55-CD97 signaling leads to circulation of splenic cDC2s and defective lymphocyte responses to blood-borne antigens. Therefore, CD97 mechanosensing of RBCs plays a role in optimizing the antigen capture and presentation functions of splenic cDC2s.