CD73 (Cluster of Differentiation 73) and the Differences Between Mice and Humans

Abstract

As vascular disease is complex and the various manifestations are influenced by differences in vascular bed architecture, exposure to shear and mechanical forces, cell types involved, and inflammatory responses, in vivo models are necessary to recapitulate the complex physiology and dynamic cellular interactions during pathogenesis. Murine knockout models are commonly used tools for investigators to study the role of a specific gene or pathway in multifaceted disease traits. Although valuable, these models are not perfect, and this is particularly true in regard to CD73 (cluster of differentiation 73), the extracellular enzyme that generates adenosine from AMP. At baseline, CD73-deficient mice do not present with an overt phenotype, whereas CD73-deficient humans present with the complex phenotype of vascular calcification, arteriomegaly and tortuosity, and calcification in small joints. In this review, we highlight the differences between the mouse and human systems and discuss the potential to leverage findings in mice to inform us on the human conditions.

CD73+ CD127high Long-Term Memory CD4 T Cells Are Highly Proliferative in Response to Recall Antigens and Are Early Targets in HIV-1 Infection

“…However, the absolute requirement of this enzyme for Treg function is unclear, with CD73 knockout mice having a relatively normal immune phenotype [ 43 ] compared to, for example, deletion of the well-defined Treg-associated inhibitory molecule, CTLA-4 [ 44 ]. In fact, rare human individuals have now been identified with loss of function mutations in the NT5E gene, leading to a lack of CD73 protein and enzymatic activity, who are characterized by arterial calcification due to vascular dysplasia, but with no reported manifestations of autoimmunity (reviewed in [ 45 ]). Furthermore, it is well described that in HIV+ subjects commencing ART, either during primary or chronic HIV-1 infection, CD4+ and CD8+ T cell activation is progressively reduced [ 46 , 47 ], but this occurs in the absence of any reconstitution of CD73+ CD4+ T cells, as previously described for ART commenced during CHI [ 12 ], and confirmed prospectively in this study for ART commenced in both CHI and PHI.…”

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

“…For instance, syngeneic and spontaneous mouse tumor models do not account for the biology of CD73s, which negatively regulates CD73 (168). A species-specific role of CD73 is also seen for arterial calcifications in humans and is not recapitulated in CD73-deficient mice (173,174). CD73 downregulation in human tumors has been described in endometrial cancer.…”

In Search of a Role for Extracellular Purine Enzymes in Bone Function

“…However, this is not always evident in other purine enzyme deficiencies in humans, such as CD73 deficiency, which has not been correlated with bone changes [ 44 ], while CD73 KO animals showed osteopenia or osteoporosis as well as spontaneous development of arthritis [ 79 ]. In this regard, it has recently been emphasized that this experimental model is not entirely adequate since there are important phenotypic differences between CD73-deficient mice and humans [ 80 ]. Therefore, more studies in humans are needed and research is now moving in this direction.…”