INHIBITION OF ANTIGEN-INDUCED T-CELL RESPONSE AND ANTIBODY-INDUCED NKCELL CYTOTOXICITY BY NKG2A - ASSOCIATION OF NKG2A WITH SHP-1 AND SHP-2 PROTEIN-TYROSINE PHOSPHATASES

Subsets of T and natural killer (NK) lymphocytes express the CD94-NKG2 A heterodimer, a receptor for major histocompatibility complex class I molecules. We show here that engagement of the CD94-NKG2A heterodimer inhibits both antigen-driven tumor necrosis factor (TNF) release and cytotoxicity on melanoma-specific human T cell clones. Similarly, CD16 -mediated NK cell cytotoxicity is extinguished by cross-linking of the CD94-NKG2A heterodimer. Combining in vivo and in vitro analysis, we r eport that both I/VxYxxL immunoreceptor tyrosine-based inhibition moti fs (ITIM) present in the NKG2A intracytoplasmic domain associate upon tyrosine phosphorylation with the protein tyrosine phosphatases SHP-1 and SHP-2, but not with the polyinositol phosphatase SHIP. Determinati on of the dissociation constant, using surface plasmon resonance analy sis, indicates that NKG2A phospho-ITIM interact directly with the SH2 domains of SHP-1 and SHP-2 with a high affinity. Engagement of the CD9 4-NKG2A heterodimer therefore appears as a protein-tyrosine phosphatas e-based strategy that negatively regulates both antigen-induced T cell response and antibody-induced NK cell cytotoxicity. Our results sugge st that this inhibitory pathway sets the threshold of T and NK cell ac tivation.