The function of a novel guidance molecule, Plexin-A1, on immune dendritic cells

Plexins (Plxns) and their ligand molecules, semaphorins were originally known as axonal guidance factors in neurons. PlxnA1, in particular, was discovered in neurons along with its soluble ligand Sema3A, another neuronal guidance cue. Since then, it has also been implicated in a variety of contexts such as cardiovascular development, carcinogenesis, or immune responses. In the immune system, PlxnA1 was originally detected in bone marrow-derived dendritic cells (DCs), regulated by Class II Transactivator (CIITA), the master regulator of MHC class II molecules. PlxnA1 expression was shown highly upregulated in mature DCs where it appeared to play a crucial role in T cell priming. The work presented here demonstrates a dual role of PlxnA1 on the surface of DCs in cognate T cell priming upon conjugation as well as in chemokine-induced DC migration. The mechanism by which PlxnA1 stimulates T cell activation upon contact involves small GTPases. PlxnA1 stimulates naïve T cell activation in an antigen-dependent manner, and augments chemotaxis of DCs towards defined chemokines attracting mature DCs, such as CCL19/21, and CXCL12, as demonstrated using DCs lacking PlxnA1. It was observed that upon T cell engagement, PlxnA1-deficient DCs contained significantly reduced levels of Rho-GTPase, leading to a defect in the polarization of actin filaments towards the interface with T cells downstream of Rho. As also suggested by a previous observation that plxnA1-/- mice showed reduced symptoms of experimental autoimmune encephalomyelitis upon challenge, PlxnA1 presents its potential to be a target for developing therapeutics against autoimmune disorders among others