Semaphorins are a family of phylogeneticallyconserved soluble and transmembrane proteins. Semaphorins were originally identified as axon guidance factors during neuronal development.Semaphorins are now known to be widely expressed mediators that play significantroles in immune responses and organ morphogenesis. Sema4D (also known as CD100) is a 150-kDa transmembrane protein of the class IV semaphorin subfamily. Sema4D is expressed at high levels in lymphoid organs, including the spleen, thymus, and lymph nodes, and in non-lymphoidorgans, such as the brain, heart, andkidney. In lymphoid organs, Sema4D is expressed abundantly by T cells but weakly by B cells. Its expression is significantly enhanced inboth T and B cells, following their respective activation. Sema4D is proteolyticallycleaved from their transmembrane form to generate 120-kDa soluble forms. Two types of receptors, Plexin-B1 and CD72, have been identified for soluble Sema4D.