CD26: A Multifaceted Molecule in Immune and Metabolic Health

CD26, also known as dipeptidyl peptidase-4 (DPP-4), is a protein with diverse biological roles. It functions as both an enzyme and a signaling molecule, influencing immune responses, glucose metabolism, and viral infections. Its presence in various tissues highlights its role in maintaining physiological balance.

Given its involvement in multiple systems, CD26 has been studied for its role in conditions such as diabetes, autoimmune disorders, and infectious diseases. Understanding its mechanisms can provide insights into disease processes and therapeutic strategies.

Structure And Localization

CD26 is a type II transmembrane glycoprotein composed of 766 amino acids. It exists as a homodimer, with each monomer containing a short cytoplasmic tail, a transmembrane domain, and a large extracellular region responsible for enzymatic and protein-binding functions. The extracellular portion includes an α/β-hydrolase domain, which houses its catalytic site, and an eight-bladed β-propeller domain that facilitates protein-protein interactions. This organization allows CD26 to function both as a membrane-bound protein and as a soluble enzyme when cleaved and released into circulation.

CD26 is widely expressed, reflecting its diverse physiological roles. It is prominently found on the surface of epithelial and endothelial cells, particularly in the kidneys, liver, and intestines, where it contributes to metabolic and regulatory processes. In the kidneys, it is present in the brush border of proximal tubules, where it plays a role in peptide metabolism. In the liver, it is found in bile canaliculi, suggesting involvement in detoxification. In the intestines, CD26 is concentrated on the luminal surface of enterocytes, where it participates in nutrient processing and absorption.

Beyond epithelial tissues, CD26 is present on endothelial cells lining blood vessels, allowing it to interact with circulating peptides and modulate their activity. A soluble form (sCD26) is detectable in plasma, where it retains enzymatic function and serves as a biomarker for various conditions. Its presence in multiple compartments underscores its functional versatility, acting both locally at the cell surface and systemically in circulation.

Enzymatic Functions

CD26 is a serine protease that selectively cleaves dipeptides from the N-terminus of peptides containing proline or alanine in the second position. This enzymatic activity regulates the bioavailability and function of numerous signaling peptides, particularly those involved in metabolism. One of its most well-characterized substrates is glucagon-like peptide-1 (GLP-1), an incretin hormone that enhances insulin secretion and suppresses glucagon release. By degrading GLP-1, CD26 modulates its glucose-lowering effects, making it a central target in diabetes therapy.

Beyond GLP-1, CD26 hydrolyzes other bioactive peptides, including glucose-dependent insulinotropic polypeptide (GIP), neuropeptide Y (NPY), and stromal cell-derived factor-1α (SDF-1α). GIP, like GLP-1, influences insulin regulation, and its degradation by CD26 affects postprandial glucose control. The cleavage of NPY, a peptide involved in appetite regulation and energy balance, links CD26 activity to broader metabolic processes. Meanwhile, SDF-1α, a chemokine involved in tissue repair and stem cell recruitment, is inactivated by CD26, affecting wound healing and vascular regeneration.

CD26 also regulates peptide hormones affecting cardiovascular and renal physiology. It degrades brain natriuretic peptide (BNP) and substance P, both of which influence vasodilation, fluid balance, and blood pressure. Inhibition of CD26 has been shown to enhance BNP activity, which may have implications for heart failure management. Similarly, the breakdown of substance P can impact pain perception and inflammatory responses, highlighting the broader physiological influence of CD26 enzymatic activity.

Immune Regulation

CD26 plays a significant role in immune activity by acting as both a co-stimulatory molecule and a regulator of cytokine signaling. It is highly expressed on activated T cells, where it influences their proliferation, differentiation, and effector functions. By interacting with adenosine deaminase (ADA), an enzyme involved in purine metabolism, CD26 helps regulate extracellular adenosine levels, which in turn affects T cell activation and immune responsiveness. Elevated CD26 expression is often observed in inflammatory conditions, suggesting its involvement in immune surveillance.

CD26 also influences antigen-presenting cells (APCs) such as dendritic cells and macrophages. Through its binding to extracellular matrix proteins like fibronectin, it facilitates immune cell migration and adhesion, essential for effective immune responses. Its role in modulating chemokine activity further underscores its impact on immune cell trafficking. By cleaving specific chemokines such as CXCL12, CD26 alters immune cell recruitment to sites of inflammation or infection.

In autoimmune diseases, CD26 expression often correlates with disease severity. Increased levels have been reported in disorders such as rheumatoid arthritis and multiple sclerosis, where heightened immune activation contributes to tissue damage. Conversely, reduced CD26 activity has been linked to immune evasion in certain cancers, as tumors exploit its immunomodulatory effects to suppress anti-tumor responses. These dual roles highlight the complexity of CD26 in immune regulation, where it can either promote or inhibit immune activity depending on the context.

Associations With Metabolic Conditions

CD26 has been closely linked to metabolic disorders, particularly those affecting glucose regulation and lipid metabolism. Its enzymatic activity influences the half-life of incretin hormones such as GLP-1 and GIP, both of which play a role in postprandial insulin secretion. Elevated CD26 activity has been observed in individuals with type 2 diabetes (T2D), where excessive degradation of these hormones contributes to impaired insulin signaling and poor glycemic control. This connection has led to the development of DPP-4 inhibitors, a class of drugs that prolong incretin activity to enhance insulin secretion and reduce blood sugar levels.

Beyond glucose metabolism, CD26 has been implicated in obesity-related dysfunctions. Studies have found that circulating levels of its soluble form (sCD26) correlate with body mass index (BMI) and adiposity, suggesting a role in energy balance. Adipose tissue expresses CD26, where it may influence lipid uptake and storage, potentially impacting fat accumulation and metabolic inflammation. Additionally, alterations in CD26 expression have been linked to dyslipidemia, with evidence indicating its involvement in triglyceride and cholesterol metabolism.

Role In Infectious Disease

CD26 plays a role in viral pathogenesis, particularly as a functional receptor for certain viruses. One of the most well-documented examples is its role in Middle East respiratory syndrome coronavirus (MERS-CoV) infection. The virus utilizes CD26 as a primary entry receptor, binding to its extracellular domain via the viral spike protein. This interaction facilitates viral attachment and internalization, allowing MERS-CoV to establish infection in host cells, particularly in the respiratory and renal systems. Given its high expression in lung and kidney tissues, this aligns with the severe pulmonary and renal complications observed in infected individuals. Understanding this mechanism has driven research into antiviral strategies that target CD26 to block viral entry.

Beyond MERS-CoV, CD26 has been implicated in modulating viral replication and immune responses in infections such as HIV and hepatitis C virus (HCV). In HIV, CD26 expression on T cells influences viral replication dynamics by affecting cytokine signaling and immune activation. Higher expression levels have been associated with increased susceptibility to infection, while downregulation has been linked to immune evasion strategies employed by the virus. Similarly, in HCV infections, CD26 activity influences viral persistence by modulating inflammatory pathways. These findings suggest that CD26 not only serves as a receptor for certain viruses but also plays a broader role in shaping host-pathogen interactions.

Genetic Variants

Genetic variations in the CD26 gene (DPP4) can influence its enzymatic activity, expression levels, and functional interactions, contributing to individual differences in disease susceptibility and treatment response. Single nucleotide polymorphisms (SNPs) within the DPP4 gene have been linked to metabolic disorders, with certain variants associated with altered glucose metabolism and increased risk of type 2 diabetes. These genetic differences may affect CD26-mediated incretin degradation, influencing glycemic control and responsiveness to DPP-4 inhibitors. Studies have identified specific SNPs that correlate with higher fasting glucose levels and insulin resistance, highlighting the potential of genetic screening to personalize therapeutic approaches.

In addition to metabolic implications, CD26 genetic variants have been studied in relation to autoimmune conditions and cardiovascular diseases. Certain polymorphisms have been associated with heightened inflammatory responses, potentially exacerbating conditions such as rheumatoid arthritis and systemic lupus erythematosus. In cardiovascular research, variations in the DPP4 gene have been linked to endothelial function and vascular integrity, with some alleles correlating with an increased risk of hypertension and atherosclerosis. These findings underscore the broader physiological impact of CD26 genetic variability, influencing metabolic, immune, and cardiovascular health.