NK cells activated through interaction with MHC class I ligand
Inhibitory receptors on the surface of NK cells prevent potential self-intolerance during interactions with major histocompatibility complex (MHC) class I molecules expressed on other cells. It is unclear, however, how NK cell self-tolerance arises, given that these inhibitory receptors are not uniformly expressed on NK cells, and are encoded by a group of hypervariable genes that are not linked with the MHC region.
"The interesting problem is, how do you match the right receptor with the right MHC class I molecule if both receptor and ligand are highly variable, and the genes are separately inherited?" asks study author Wayne M. Yokoyama, MD, the Sam J. Levin and Audrey Loew Levin professor of research in arthritis and professor of medicine and of pathology and immunity at Washington University in St. Louis, Missouri. "There must be some kind of pairing mechanism to bring the right combinations together."
The key, Dr. Yokoyama and his colleagues find, is that NK cells require "licensing" to become fully competent to carry out their immune functions, and this license is granted only to NK cells that express inhibitory receptors that can interact with self-MHC molecules.
"We discovered that the inhibitory receptor on the NK cell itself recognizes the MHC class I molecule, and when it does, it ironically provides a positive signal, resulting in the development of a fully functional NK cell. The fully competent NK cell is then able to recognize self through the same receptor that allowed its development," Dr. Yokoyama tells CIAOMed. In contrast, he explains, "unlicensed" NK cells do not have inhibitory receptors that recognize self-MHC molecules, and so are not fully functional.
However, "if an invader tries to alter the expression of MHC class I genes, as happens when viruses alter MHC class I to evade T cells, then the NK cell is released from inhibition, so it can kill off the invader and induce an inflammatory response," he explains.
"This concept helps explain why some human patients who are infected with hepatitis C can clear the infection, whereas others who are infected with the virus have a lifelong infection," Dr. Yokohama says. "Genes for the human forms of these receptors and HLA (human MHC ) are associated with resolution of an otherwise chronic infection, so more potent NK cells may be able to eradicate viral infections."
Findings may shed light on autoimmunity
"It's also possible that this type of tolerance mechanism is altered in patients with autoimmune disease," Dr. Yokohama says. "There could be autoimmune NK cells that are inadvertently licensed, so they are fully armed, but they can't be turned off by MHC class I as they should be under normal circumstances.
"Clearly we are interested in understanding how this works, but we are also trying to see if we can come up with a test for humans to see whether we can find licensed human NK cells, and look at them in the context of autoimmunity, chronic infections, and bone marrow transplantation."
Reference
- Kim S, Poursine-Laurent J, Truscott SM, et al. Licensing of natural killer cells by host major histocompatibility complex class 1 molecules. Nature. 2005;436:709-713.