Background/Purpose: CD73 is a surface nucleotidase that extends into the extracellular space where it generates adenosine from AMP. By regulating a cell’s “purinergic halo,” CD73 contributes to the maintenance of immune and vascular homeostasis. Although CD73 is known to be expressed on the surface of T cells, endothelial cells, and myeloid-lineage cells, it has yet to receive intensive study in the context of lupus.

Methods: In C57BL/6 Fas^lpr/lpr (B6.lpr) mice, we generated littermates of 3 genotypes: CD73^+/+, CD73^+/-, and CD73^-/-. Autoantibody levels were measured at 16 and 32 weeks of age. At 32 weeks of age, splenocyte activation/polarization and endothelial function were also characterized. In parallel to the B6.lpr studies, we also assessed the role of CD73 in an inducible model of lupus. C57BL/6 mice with no lupus predisposition (CD73^+/+, CD73^+/-, and CD73^-/-) received topical dosing of the TLR7/8 agonist R848 (resiquimod) three times weekly. Autoantibody levels were measured 4 and 8 weeks after the initiation of treatment.

Results: As compared with B6.lpr CD73^+/+ mice, B6.lpr mice with CD73 deficiency (either partial or complete) demonstrated a greater than 2-fold increase in serum anti-double-stranded-DNA antibodies at both 16 and 32 weeks; this was despite no difference in total IgG levels between groups. Beyond antibodies, CD73-deficient B6.lpr mice demonstrated additional abnormalities in peripheral blood including relative lymphopenia (5-fold decrease), neutropenia (4-fold decrease), and elevated levels of cell-free DNA. In 32-week-old B6.lpr CD73^+/+ mice, the majority of CD73-positive cells infiltrating spleens were either T cells (CD4⁺ and double-negative) or CD11b⁺Ly6C⁺ monocytes (likely myeloid-derived suppressor cells/MDSCs). In contrast, surface CD73 was not detected on CD8⁺ T cells or granulocytic MDSCs. Endothelial function was measured in the aortas of 32-week-old B6.lpr mice by ex vivo exposure of aortic rings to acetylcholine in a wire myography system. As compared with CD73^+/+ mice, CD73 deficiency resulted in impaired vessel-wall relaxation consistent with decreased nitric oxide production and resultant endothelial dysfunction. In the R848-inducible model of lupus, anti-double-stranded-DNA antibody production was again potentiated by CD73 deficiency. Studies are now underway to comprehensively phenotype the spleens of both mouse models in order to understand the dominant CD73-expressing suppressive cell type in lupus.

Conclusion: These data reveal a protective role for CD73 in lupus autoimmunity and vascular disease, and are consistent with a model whereby a key suppressive cell type (either CD4⁺ regulatory T cells or monocytic MDSCs) wields CD73 and adenosine to suppress B cell function. These data also suggest that novel therapeutic strategies might harness purinergic signaling to limit the damage inflicted by lupus upon organs and blood vessels.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ectonucleotidase-cd73-suppresses-autoantibody-production-and-arterial-vasculopathy-in-murine-lupus/