Semaphorin 4D as a guidance molecule in the immune system

Semaphorin 4D (Sema4D) is a classic member of the semaphorin family involved in axonal guidance processes. The key effects of Sema4D in neurons are mediated by high affinity plexin receptors and are associated with cytoskeleton rearrangement, leading to growth cone collapse or regulation of cell migration. Along with this, the semaphorin is widely represented in the immune system and has a pronounced immunoregulatory activity. The involvement of Sema4D in the control of immune cell migration was shown almost twenty years ago, in one of the first studies of semaphorin. The emergence of such work was quite predictable, since the most well-known effects of Sema4D outside the immune system were associated precisely with the control of cell motility. However, after identification of CD72 as a specific Sema4D receptor in the immune system, studies of the immunoregulatory activity of semaphorin focused on its CD72-dependent effects unrelated to cytoskeleton rearrangement, and this trend continues up to now. Nevertheless, a number of recent studies demonstrating the presence of plexin receptors for Sema4D in the immune system forces us to return to the question of whether this semaphorin can play its classic role of a guidance molecule in relation to immune cells too. The review discusses Sema4D involvement in the control of immune cell migration, as well as the mechanisms of these effects and their potential contribution to the development and function of immune system.