Regulation of immune cell responses by semaphorins and their receptors

Abstract

Semaphorins were originally identified as axon guidance factors involved in the development of the neuronal system. However, accumulating evidence indicates that several members of semaphorins, so-called 'immune semaphorins', are crucially involved in various phases of immune responses. These semaphorins regulate both immune cell interactions and immune cell trafficking during physiological and pathological immune responses. Here, we review the following two functional aspects of semaphorins and their receptors in immune responses: their functions in cell-cell interactions and their involvement in immune cell trafficking.

Figure 1

Representative immune semaphorins and their receptors in lymphoid and non-lymphoid cells. Sema3A binds to neuropilin-1 with high affinity to assemble a NP-1/plexin-A1 receptor complex and involves in the axon guidance events. Sema4D binds to plexin-B1 in the brain and transduces chemorepulsive signals. In the immune system, Sema4D uses CD72 as a functional receptor in B cells and DCs and enhances the activation of B cells and DCs. Sema4A binds TIM-2 and is involved in T-cell activation and differentiation in the immune system. In the non-immune system, however, Sema4A recognizes plexin-B proteins and plexin-D1. Sema6D exerts different biological activities through plexin-A1, depending on its coreceptors. During chick embryogenesis, plexin-A1 differentially associates with off-track and VEGFR2, and these receptor complexes have distinct functions in heart development. In the immune system, plexin-A1 forms a receptor complex with TREM-2 and DAP12 and, after Sema6D binds, this complex transduces signals that stimulate DCs and osteoclasts. Sema7A uses β1 integrin as receptors in both the nervous and immune systems. In the immune system, Sema7A expressed on activated T cells stimulates macrophages through α1β1 integrin to promote inflammatory responses. DC, dendritic cell; DAP12, DNAX-activating protein 12; NP-1, neuropilin-1; OTK, off-track kinase; TIM-2, T-cell immunoglobulin and mucin domain-containing protein 2; TREM-2, triggering receptor expressed on myeloid cells 2; VEGFR2, vascular endothelial growth factor receptor 2.