CD40: a gatekeeper of natural antibody production in atherosclerosis

The National Heart, Lung, and Blood Institute awarded Mayo Clinic $820,111 on August 15, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to investigate the cell-specific role of the CD40L-CD40 co-stimulatory dyad in modulating atherosclerosis and natural antibody production.

The project examines how CD40 expression on B1 cells—innate B cells that produce atheroprotective anti-oxidation-specific-epitope (OSE) immunoglobulin M—protects against atherosclerosis by maintaining B1 cell metabolic homeostasis during hyperlipidemia. The research builds on prior findings showing that CD40 deficiency on B cells increases atherosclerosis through reduced B1 cell populations and impaired anti-OSE IgM responses, while patients with severe coronary artery disease demonstrate decreased CD40 expression on putative B1 cells. The work targets cell-type-specific CD40L and CD40 signaling pathways as potential immunotherapeutic targets to combat atherosclerosis while preserving CD40L-CD40 interactions required for maintaining proper immunity.

Performance of the work occurs at Mayo Clinic in Rochester, Minnesota, with a period of performance running from August 15, 2026, through May 31, 2030. This is a Project Grant, the standard assistance type for investigator-initiated biomedical research under the NHLBI portfolio.

Abstract

Targeting innate and adaptive immune responses in atherosclerotic cardiovascular disease (CVD) has been proven successful in clinical proof-of-concept trials. To pursue immunotherapeutic solutions in the CVD field, detailed insights into cell-specific immune responses in atherosclerosis are needed. The CO-stimulatory CD40L- CD40 dyad is a master regulator of immune responses and atherosclerosis. We have identified an important, cell divergent role for the CO-stimulatory CD40L-CD40 dyad in modulating atherosclerosis. Whereas deficiency of T- cell CD40L decreases atherosclerosis and induces plaque stability, deficiency of platelet CD40L only affects atherothrombosis. Deficiency of macrophage CD40 reduces atherosclerosis by enhancing efferocytosis and reducing necrotic core content, while deficiency of dendritic cell CD40 impairs TH1 responses and induces an increase in plaque collagen content. Understanding the cell-type specific actions and signaling pathways of CD40L and CD40 is important: CD40(L) expressing cell types and cell-type specific signaling intermediates can be targeted to combat atherosclerosis and limit unwanted side effects, as this strategy has the potential to leave CD40L-CD40 interactions required for maintaining proper immunity intact. CD40 is highly expressed on B cells, and we found that depletion of CD40 on B cells increases atherosclerosis, which we found to be caused by a reduction in B1 cells, the innate type B cell that produces atheroprotective anti- oxidation specific epitope (OSE) igms. CD40 deficient B1 cells have an impaired cellular metabolism, thereby hampering adequate anti-OSE IGM responses. We could show that patients with severe coronary artery disease showed a decrease in CD40 on their putative B1 cells. We hypothesize that B1 cell CD40 protects against atherosclerosis, by maintaining B1 cell metabolic homeostasis during hyperlipidemia, thereby warranting adequate atheroprotective anti-OSE IGM responses, and that reduced CD40 expression on B1 cells is associated with CVD in humans. In aim 1 will study the effects of deficiency of B1, B1A and B1B cell CD40 in early, intermediate, and advanced stages of atherosclerosis and we will delineate mechanisms how CD40 maintains B1 cell homeostasis. In aim 2, we will investigate the potential of B1 cell CD40 as biomarker for coronary artery disease in our UVA CAD patient cohorts. Understanding the role of CD40 in mediating B1 cell function in atherosclerosis will unlock its translational potential as immunotherapeutic target and biomarker for atherosclerotic CVD.