Splenic cDC1 efferocytosis and cross-presentation to CD8 T cells are promoted by GPR34 and lysophosphatidylserine

Spleen conventional dendritic cells type 1 (cDC1) take up apoptotic cells (AC) and cross-present associated antigens to CD8 T cells. The receptors promoting AC uptake are incompletely defined. Here, we tested the function of GPR34, a receptor that responds to the phosphatidylserine (PS) catabolite lysoPS. GPR34 deficiency led to reduced AC uptake by cDC1 but not cDC2 or macrophages. Uptake of soluble antigen or heat-killed bacteria was unaffected, whereas uptake of eryptotic RBCs was reduced. Using AC harboring OVA, activation and proliferation of OT-I T cells were compromised in GPR34-deficient mice. Reciprocally, GPR34 overexpression led to enhanced AC uptake and OT-I proliferation. The enzymes PLA1A and ABHD16A have been implicated in generating lysoPS that can act on GPR34. PLA1A but not ABHD16A deficiency was associated with a reduced OT-I response to AC-associated OVA. In conclusion, we identify a receptor requirement for cDC1 efferocytosis and cross-presentation and suggest a model where PLA1A catabolizes PS on AC to generate GPR34 ligands.