LAIR and collagens in immune regulation

Abstract

The immune system constantly receives opposing signals that on the one side activate immune cells allowing them to eradicate diseased cells and pathogens, and on the other side inhibit these same cells to limit and ultimately terminate an immune response. A correct balance is crucial for effective defence against pathogens without affecting healthy tissues. One of the mechanisms of negative regulation in the immune system is provided by specialized inhibitory receptors that upon interaction with their ligands attenuate activation signals initiated by activating receptors. Loss of inhibitory signaling is often associated with autoreactivity and unchecked inflammatory responses, illustrating the essential role these systems play in immune regulation. This thesis is focused on the function of such an inhibitory receptor called leukocyte-associated immunoglobulin-like receptor (LAIR)-1, which is expressed on most immune cells in peripheral blood. Although the inhibitory potential and mechanisms of LAIR-1 inhibition are well established, the actual function of the receptor in vivo remains unknown due the lack of animal models and the unknown identity of the LAIR-1 ligand. In the first part we identified and characterized mouse and rat LAIR-1 orthologues of human LAIR-1. Like human LAIR-1, mouse LAIR-1 is expressed on immune cells and functions as an inhibitory receptor. Furthermore we show that human and mouse LAIR-1 bind to similar, but not identical, cytoplasmic signalling effector molecules. In the second part we identified collagens as ligands for the LAIR-1 molecules. Both transmembrane and extracellular matrix collagens interact with LAIR-1 and the interaction results in inhibition of immune cell functions via LAIR-1. Our data reveal a novel mechanism of peripheral immune regulation by inhibitory immune receptors binding to extracellular matrix collagens. Additionally, we studied the functional interaction of LAIR-1 and collagens by using synthetic trimeric collagen peptides overlapping the entire human collagen II and III proteins. We show that LAIR-1 binds to multiple sites on these collagens and that the relative content of collagen-specific glycine-proline-hydroxyproline triplets in the proteins is associated with increased LAIR-1 binding. Besides the transmembrane LAIR-1, humans encode soluble LAIR-2 receptors. For the first time we provide evidence that LAIR-2 is expressed in humans as a soluble collagen receptor and that the molecule can block the collagen/LAIR-1 interaction. Hence, we hypothesize that soluble LAIR-2 may function as a natural competitor for LAIR-1 in vivo, thereby regulating its inhibitory potential. Further studies should aim at dissecting the in vivo role of LAIR-1 and LAIR-2 in normal physiology and disease. Furthermore, detailed studies on the biochemical interaction between collagens and LAIR may allow rational design of new and potent research tools and could result in the development of therapeutics which exploits collagen/LAIR interactions.