Heparan Sulfate Proteoglycans in Immunity

ABSTRACT

In immune cells, heparin was first identified in mast cells in the 1940s, followed by the discovery of heparan sulfate in lymphocytes and granulocytes during the 1970s and 1980s. Subsequent decades of research have revealed how heparan sulfate and heparin, conjugated to core proteins as heparan sulfate proteoglycans (HSPGs), act as versatile modulators of immune function. It is now known that HSPGs are expressed by virtually all leukocytes and bind hundreds of immune mediators, including cytokines, proteases, growth factors, antimicrobial peptides, and extracellular matrix (ECM) components. HSPGs on leukocyte surfaces and within intracellular granules, as well as those on non‐immune cells and within the ECM, shape immune cell development and responses to both endogenous and exogenous threats. Because immune activity must be tightly controlled to prevent collateral tissue damage, HSPGs play critical modulatory roles—facilitating, competing, protecting, presenting, or allosterically regulating immune factors. Consequently, mutations in HSPG core proteins and heparan sulfate biosynthetic enzymes, or dysregulation of HSPG‐mediated immune interactions, contribute to diverse pathologies, including primary immunodeficiencies, autoimmune disease, infection, inflammatory tissue injury, allergy, and cancer. This review will highlight key mechanisms through which HSPGs regulate the development and function of major immune cell types.