Semaphorins as Modulators of Leukocyte Migration

The semaphorin gene family encodes proteins that are best known for their function as axon guidance molecules in the developing nervous system. The long term objective of the studies described in this application is the characterization of semaphorin function outside of the nervous system, in cells involved in humane response. Semaphorin expression has been found in many tissues outside the CNS, including the heart, bones, thymus, and spleen. Semaphorin-like genes have also been identified in two families of viruses, poxviridae and herpesviridae, each of which is known to possess xenologs of host genes that are integral to normal immune response. Several of these viral proteins blunt the host's organism's immune response to infection, prevent apoptosis of the infected cell, or promote the cell division in surrounding tissue. The recent identification of an immune-specific semaphorin, CD100 [sema4d], lends further support to the idea that semaphorins serve as immunomodulators. Our preliminary studies have shown that both viral semaphorins inhibit the migration of human T cells and that human SEMA3A can inhibit the migration of human neutrophils. We propose to assess the expression of semaphorin receptor genes in T cells, B cells, monocytes and neutrophils, examine the expression of SEMA3A, SEMA4D, and SEMA7A to modulate the migration of candidate natural killer cells, T cells, B cells, monocytes, and neutrophils in vitro, work that will provide an important foundation for future studies of role of semaphorins in leukocyte homing in vivo. As leukocytes are the primary cells that respond to infection, destroy nascent tumors, and mediate inflammatory response, characterization of molecules that regulate leukocyte function during development, homeostasis, and activation has considerable medical interest as the basis of therapies for combating viral infections, tumors, and inflammation.