REQUIREMENT FOR JAK3 IN MATURE T-CELLS - ITS ROLE IN REGULATION OF T-CELL HOMEOSTASIS

The tyrosine kinase Jak3 plays a key role in transducing signals from the IL-2, -4, -7, -9, and -15 receptors, Mice lacking Jak3 exhibit a p rofound, early block in both B and T cell development. To examine the mechanisms whereby Jak3 influences T cell function, we have reconstitu ted thymic development in Jak3(-/-) animals by introducing a Jak3 tran sgene in which expression was driven by the lck proximal promoter, Thy mic reconstitution required Jak3 kinase activity, as catalytically ina ctive Jak3 did not restore early thymic development, Furthermore, the thymus-restricted expression pattern of the transgene allowed us to as sess the requirement for Jak3 in peripheral T cells, In these mice, lo ss of Jak3 expression was associated with a failure to proliferate in response to antigen receptor crosslinking, the accumulation of T cells manifesting an activated cell surface phenotype, and an increased CD4 /CD8 ratio among peripheral T cells, all of which are characteristics that were observed in Jak3(-/-) animals. Finally, we present data whic h suggest that peripheral T cells proliferate more rapidly in vivo and also undergo apoptosis more rapidly, upon loss of Jak3, Hence Jak3 ex erts effects on mature peripheral T lymphocytes, as well as on thymocy tes, resulting in the proper maintenance of circulating, quiescent cel ls.