Class IV semaphorin Sema4A enhances T-cell activation and interacts with Tim-2

Semaphorins are a family of phylogenetically conserved soluble and transmembrane proteins1,2. Although many soluble semaphorins deliver guidance cues to migrating axons during neuronal development3,4,5, some members are involved in immune responses6,7,8,9. For example, CD100 (also known as Sema4D), a class IV transmembrane semaphorin, signals through CD72 to effect nonredundant roles in immune responses7,10,11,12,13 in a ligand–receptor system that is distinct from any seen previously in the nervous system14,15. Here we report that the class IV semaphorin Sema4A, which is expressed in dendritic cells and B cells, enhances the in vitro activation and differentiation of T cells and the in vivo generation of antigen-specific T cells. Treating mice with monoclonal antibodies against Sema4A blocks the development of an experimental autoimmune encephalomyelitis that is induced by an antigenic peptide derived from myelin oligodendrocyte glycoprotein. In addition, expression cloning shows that the Sema4A receptor is Tim-2, a member of the family of T-cell immunoglobulin domain and mucin domain (Tim) proteins that is expressed on activated T cells.