GRANZYME-A RELEASED UPON STIMULATION OF CYTOTOXIC T-LYMPHOCYTES ACTIVATES THE THROMBIN RECEPTOR ON NEURONAL CELLS AND ASTROCYTES

Granzymes are a family of serine proteases that are harbored in cutopl asmic granules of activated T lymphocytes and are released upon target cell interaction. Immediate and complete neurite retraction was induc ed in a mouse neuronal cell line when total extracts of granule protei ns were added. This activity was isolated and identified as granzyme A . This protease not only induced neurite retraction at nanomolar conce ntrations but also reversed the stellation of astrocytes. Both effects were critically dependent on the esterolytic activity of granzyme A. As neurite retraction is known to be induced by thrombin, possible cle avage and activation of the thrombin receptor were investigated. A syn thetic peptide span ning the N-terminal thrombin receptor activation s equence was cleaved by granzyme A at the authentic thrombin cleavage s ite Leu-Asp-Pro-Arg-Ser. Antibodies to the thrombin receptor inhibited both thrombin and granzyme A-mediated neurite retraction. Thus, T-cel l-released granzyme A induces cellular responses by activation of the thrombin receptor. As brain-infiltrating CD4(+) lymphocytes are the ef fector cells in experimental allergic encephalomyelitis, granzyme A re leased in the brain may contribute to the etiology of autoimmune disor ders in the nervous system.