CD69-triggered ERK activation and functions are negatively regulated by CD94/NKG2-A inhibitory receptor

CD69 represents a functional triggering molecule on activated NK and T cell s, capable of inducing cytotoxic activity and costimulating cytokine produc tion. It belongs to the C-lectin type superfamily, and its gene maps in the NK gene complex, close to other genes coding for NK receptors;CD94/NKG2-A complex is the inhibitory receptor for the non classical MHC class I molecu le HLA-E on human NK cells. To investigate CD69-initiated signal transducti on pathways, and to evaluate CD94/NKG2-A interference on CD69 triggering ab ility, we have generated transfectants expressing both receptors in the RBL cell line. Here we report that CD69 engagement leads to the activation of extracellular signal-regulated kinase (ERK) enzymes belonging to the MAPK f amily, and that this event is required for CD69-mediated cell degranulation . Moreover, we show that the co-engagement of CD94/NKG2-A inhibitory recept or effectively suppresses both CD69-triggered cell degranulation in RBL tra nsfectants, through the inhibition of ERK activation, and CD69-induced cyto toxicity in human NK cells; Thus, here we provide new information on the mo lecular mechanisms initiated by CD69 activation receptor, and show that CD6 9-initiated signaling pathways and functional activity are negatively regul ated by CD94/NKG2-A inhibitory complex.