Ly49 is a family of membrane C-type lectin-like receptors expressed mainly on NK cells but also on other immune cells, NKT cells, uterine NK cells. Their primary role is to bind MHC-I molecules to distinguish between self healthy cells and infected or altered cells. Ly49 family is coded by Klra gene cluster and include genes for both inhibitory and activating receptors, but most of them are inhibitory. Inhibitory Ly49 receptors play role in the recognition of self cells and thus maintain self-tolerance and prevent autoimmunity by suppressing NK cell activation. On the other hand, activating receptors recogniseligands from cancer or viral infected cells and are used when cells lack or have abnormal expression of MHC-I molecules, which activate cytokine production and cytotoxic activity of NK and immune cells. Ly49 receptors are expressed in some mammals including rodents, cattle, some primates but not in humans. Only one human gene homologous to rodent Ly49 receptors is found in the human genome, KLRA1P, however, it represents a non-functional pseudogene. However killer cell immunoglobulin-like receptors have the same function in humans. They have different molecular structure but recognise HLA class I molecules as ligands and include both inhibitory and activating receptors.
Function
Role in NK cells
Function of NK cells is to kill viral infected or other way abnormal cells, therefore they must have precisely regulated system of recognising self-cells to prevent their destruction. They express several types of inhibitory and activating receptors on their surface including Ly49 receptor family, which have role in NK cell licencing, antiviral and antitumor immunity, each of them will be described below. NK cells are activated when signal from activating receptors outweighs inhibitory signals. This could happen when activating receptors recognise viral proteins presented on infected cell surface. Some Ly49 receptors have evolved to recognise specific viral proteins, for exapmle Ly49H binds to murine cytomegalovirus glycoprotein m157. Mouse strains without Ly49H are more susceptible to MCMV infection. In addition these Ly49H positive NK cells have properties of MCMV specific memory NK cells and react better during secondary MCMV infections. Another example of NK cell activation is recognition of tumor cells, which stop expressing MHC I molecules in order to avoid killing by cytotoxic T lymphocytes. Inhibitory receptors of NK cells don't obtain signal resulting in cell activation via activating receptors. This mechanism describes missing-self hypothesis. In order to be fully functional and have cytotoxic activity, NK cells need to get signals from self-MHC I molecules on inhibitory Ly49 receptors in rodents especially during their development. This educational process prevents generation of autoreactive NK cells and it was called „NK cell licencing“ by Yokoyama and colleagues. If inhibitory Ly49 receptors miss the signal from MHCI during their development, they are unlicenced and they don't react to stimulation on activating receptors. But this hyporesponsive state isn't definite and they can be re-educated in certain conditions. Besides, it has been shown un-educated cells can be activated by certain acute viral infections or by some tumors and kill these cells more efficiently than educated cells.
Receptor types
Inhibitory receptors
Inhibitory receptors play role in the NK cell licensing and are important for recognition and tolerance of self cells. Stimulation of inhibitory receptors leads to fosforylation of immunoreceptor tyrosine‐based inhibitory motif, located in the cytoplasmic part of these receptors. Phosphorylated Ly49 molecule recruits the src homology 2 domain containing protein phosphataseSHP-1, which defosforylates ITIM and thus prevents cell activation. Inhibitory receptors include Ly49A, B, C, E, G, Q.
Activating receptors
Activating receptors are involved in antiviral and antitumor immunity. They signal through immunoreceptor tyrosine-based activation motif which is part of an associated molecule DAP-12 attached to arginine in the transmembrane segment of Ly49. After stimulation of the receptor and phosphorylation of ITAM, SH2 domain with protein kinase is recruited and that starts kinase signaling cascade leading to activating cell effector functions. Activating receptors include Ly49D, H, L.
