This project involves the study of a rapidly emerging group of immune receptors. Many families of inhibitory immune receptors have recently been identified in both mice and humans. Interestingly, within each of these inhibitory families of receptors, there are proteins that have lost the inhibitory domains. Instead these receptors have gained a positively charged amino acid within their transmembrane domain, suggesting that they may interact with signal transduction chains and transmit positive signals. In this project, we study the signal transduction and biochemistry of these putative positive regulators of immune cell function. Of the Ly49s characterized to date, only two, Ly49D and H, have been shown to interact with a newly described signaling chain, DAP12. We have extensively characterized DAP12 signal transduction and will continue to do so using a variety of gene targeted mice. In addition, we have used a chimeric receptor approach to ask if the any of the recently described family of immunoglobulin superfamily inhibitory receptors, termed Paired Immunoglobulin-like Receptors (PIR), act through DAP12. These studies were recently published and demonstrated that PIR physically interact with the gamma chain of the Fc epsilon receptor, but not DAP12, in murine macrophages. Our studies of putative activation and inhibitory receptors in monocytes have led us to examine the biochemistry of CD33, a myeloid specific adhesion molecule. We have submitted for publication work demonstrating the phosphorylation of CD33, its association with protein tyrosine phosphatases, and its ability to function as an inhibitory receptor. In addition, we have cloned a CD33-like receptor and are studying its expression and function. - macrophages, Natural killer cells, Phosphorylation, Protein-Tyrosine Kinase, Signal Transduction, protein tyrosine phosphatase,