The overall objective of this R21 research project is to elucidate a new pathogenic mechanism involved in multiple sclerosis (MS) so that new therapies can be developed to treat the disease. While MS is triggered by a number of genetic and environmental factors, a common pathogenic mechanism is the infiltration of the central nervous system (CNS) by circulating leukocytes. How leukocytes migrate into CNS is not well understood. It is believed that an internal cellular pilot, akin to a ship’s maritime pilot, guides leukocyte migration into nervous tissue; but the nature of this cellular pilot remains poorly defined. This R21 application is inspired by our recent discovery that murine leukocytes deficient in the TIPE (tumor necrosis factor-a-induced protein 8-like) family of proteins are defective in directed migration: they are unable to migrate toward chemoattractants or into nervous tissue to cause encephalomyelitis despite their normal activation status. TIPE proteins are risk factors for both multiple sclerosis and plantar fasciitis as revealed from recent genome-wide association studies (GWAS), and their expression is dysregulated in a number of human diseases including autoimmune diseases. We initially cloned the TIPE2 gene from the spinal cord of mice with experimental autoimmune encephalomyelitis (EAE) and found that it was preferentially expressed by leukocytes. We then generated mice deficient in TIPE2 and found that they were significantly resistant to EAE. Unexpectedly, TIPE-deficient T cells have no defect in activation, but are severely compromised in their ability to migrate into nervous tissue and to induce EAE. In this proposal, we will test the hypotheses that (i) TIPE proteins control the migration of human T cells, and (ii) TIPE family is the pilot of human T cells.