Semaphorins are a family of soluble and membrane associated proteins characterized by a conserved “sema” domain. They were originally described as axonal growth and guidance proteins required to guide neuronal axons to the right targets. Today semaphorins are known to possess pleiotropic and important functions in several physiological and pathological processes, including heart development, vascular growth, tumor progression, immune cell regulation, angiogenesis and vasculogenesis. To date, more than 20 types of semaphorin proteins have been identified and classified into eight subclasses^1,2. The conserved “sema” domain of the protein includes arginine–glycine–aspartate sequences. The C-terminal region includes an IgG-like domain, a transmembrane domain, and a short cytoplasmic tail that contains one tyrosine phosphorylation site and multiple sites for serine–threonine phosphorylation^1,2.

Semaphorin 4D (Sema4D), also known as CD100, is a 150-kDa membrane‐associated‐type class IV semaphorin and was the first semaphorin shown to have immune regulatory activity. Other Sema4D functions include inactivation of platelets, stimulation of angiogenesis, and regulation of bone formation. Sema4D is expressed in many tissues including the brain, kidney, and heart. Sema4D is expressed in resting T cells, and expression is increased upon cellular activation³.