Influence of T cell genotype/phenotype in atherosclerotic cardiovascular disease

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PROJECT SUMMARY Atherosclerotic cardiovascular disease (ASCVD) is an inflammatory disease of unclear pathogenesis that remains the leading cause of morbidity and mortality throughout the world. Immune responses play a central role in the evolution of this chronic disease, and CD4+CD25+Foxp3+ regulatory T cells (Tregs) exhibit critical functions to regulate inflammation. We have shown the level of expression of CD39, an immunosuppressive ectonucleotidase, on Tregs to be genetically associated in humans with specific single nucleotide polymorphisms (SNPs). Although select SNPs for CD39 have been linked to Crohn disease, no studies have examined whether alterations in Treg CD39 catalytic activity, and changes in extracellular ATP scavenging with adenosine generation, impact manifestations of ASCVD. Similarly, a naturally occurring antisense ENTPD1-AS1 has been shown to decrease CD39 expression in Crohn’s patient Tregs. Inhibition of ENTPD1-AS1 with a specific self- delivering FANA CD39 antisense (FANA-CD39-AS) oligonucleotide were shown to increase CD39 expression, providing a therapeutic option to modulate Treg phenotype. Our overall experimental goal is to elucidate the impact of genetic regulation of Treg CD39 expression in ASCVD. The central hypothesis is that genetic mutations resulting in decreased Treg CD39 activity and altered purinergic responses drive ASCVD due to the inability to adequately resolve inflammation. We will test this hypothesis by conducting functional genomic experiments, in addition to using novel murine experimental model systems, and develop clinical studies, examining isolated cells and patient biospecimens. The proposal consists of two Aims. In SA1, our investigative team will determine how Treg expression of CD39 activity impacts atherosclerosis in a validated experimental system. This will be done using CD39 Treg-specific conditional knock-down and knockout murine models with multiple readouts of T cell and myeloid activation responses, and adoptive transfer studies, In SA2, we will examine the regulation of CD39 expression on human Tregs and examine the impact of CD39 modulation on immune function and inflammation in clinical studies of ASCVD. We have assembled a collaborative team with clinical and experimental expertise in ASCVD, immunology, vascular biology, genetics, and biostatistics. Completion of the proposed aims will develop understanding of the role of Tregs, and specifically expression of CD39 and altered purinergic responses, in ASCVD, this most important and significant disease. Translation to clinical practice will be facilitated by identification of important biomarkers and novel targets, inclusive of CD39 and related pathways of adenosinergic signaling, for therapeutic intervention in ASCVD.