Mechanisms of LAIR-1 mediated inhibition of immune function

Abstract

The mammalian immune system has to eliminate pathogens, while preventing damage to the host. An adequate function of the immune system therefore requires the coordinate action of activating and inhibitory signals. Loss of inhibitory signals may lead to chronic inflammation or auto-immune disease. A part of the negative regulation of the immune system is mediated by receptors that contain so-called Immunoreceptor Tyrosine-based Inhibitory Motifs (ITIMs). In the past decade, a large number of ITIM-bearing receptors have been identified on different types of immune cells. However, while studies in mice revealed non-redundant functions in the regulation of the immune system, it is still incompletely understood how these receptors exert their function. The research described in this thesis focuses on the function of Leukocyte-Associated Ig-like Receptor (LAIR)-1, an inhibitory receptor expressed on most immune cells in peripheral blood. In the first part, we show that the expression of LAIR-1 on one type of immune cells, neutrophils, is regulated during differentiation and activation, suggesting that LAIR-1 may regulate both neutrophil differentiation and function. In the second part, the mechanisms by which LAIR-1 inhibits immune cell function have been investigated. LAIR-1 contains two ITIMs that recruit the phosphatases SHP-1 and SHP-2 upon phosphorylation of the receptor. These phosphatases are generally believed to mediate the inhibitory function of ITIM-bearing receptors by inactivating key components involved in cellular activation. By separate mutation of the ITIMs of LAIR-1, we found that they contribute differentially to the recruitment of the phosphatases and to the inhibitory function. We also found that LAIR-1 was still functional in cells lacking both SHP-1 and SHP-2, indicating that LAIR-1 may recruit additional molecules. By screening for molecules that specifically bound to phosphorylated LAIR-1, we identified Csk, a known regulator of immune cells, as a third LAIR-1 interacting protein. Further research is required to investigate the contribution of SHP-1, SHP-2 and Csk to the function of LAIR-1 and other ITIM-bearing receptors. Ultimately, such research will provide more insight in the mechanisms that regulate the immune system.