Copyright © by The Rockefeller University PressWe investigated the in vivo role of CD69 by analyzing the susceptibility of CD69 / mice to tumors. CD69 / mice challenged with MHC class I tumors (RMA-S and RM-1) showed greatly reduced tumor growth and prolonged survival compared with wild-type (WT) mice. The enhanced anti–tumor response was NK cell and T lymphocyte–mediated, and was due, at least in part, to an increase in local lymphocytes. Resistance of CD69 / mice to MHC class I tumor growth was also associated with increased production of the chemokine MCP-1, diminished TGF- production, and decreased lymphocyte apoptosis. Moreover, the in vivo blockade of TGF- in WT mice resulted in enhanced anti–tumor response. In addition, CD69 engagement induced NK and T cell production of TGF- , directly linking CD69 signaling to TGF- regulation. Furthermore, anti-CD69 antibody treatment in WT mice induced a specific down-regulation in CD69 expression that resulted in augmented anti–tumor response. These data unmask a novel role for CD69 as a negative regulator of anti–tumor responses and show the possibility of a novel approach for the therapy of tumors.Peer reviewed