Considering Peptide Tuning of Natural Killer (NK) Cells

Natural killer (NK) cells are cytotoxic lymphocytes — important immune cells of the innate immune system. NK cells are increasingly understood to be significant in the way the body responds to viruses, such as hepatitis, HIV and tumors. In fact, some scientists are eyeing NK cells as potential therapeutic agents in cellular therapy studies.

Salim Khakoo, MD, professor of Hepatology at University of Southampton, UK, and Jayajit Das, PhD, principal investigator in the Battelle Center for Mathematical Medicine, have been collaborating to understand how NK cells and their receptors work at the molecular level.

They’ve recently published a review focusing on the role of the peptides presented by MHC-I in activating NK cells. Two gene families of receptors — killer cell immunoglobulin-like receptors (KIRs) and the C-type lectin-like CD94:NKG2 receptors — are primarily responsible for communication between MCH1 and the NK cells.

The CD94 family of receptors is well conserved evolutionarily, and scientists think it may downregulate NK cells. The KIRs, however, have rapid evolution likely driven by viruses. Peptide changes for KIRs lead to NK activation.

Drs. Khakoo and Das hypothesize that the peptides presented by MHC1 determine the cascade of cellular reactions that result from the binding of NK receptors to MHC1 and that this recognition of peptides is favorable for humans.

“We know that NK cells play a powerful role in how a person’s body reacts to cancer and viral infections,” says Dr. Khakoo. “We’ve been interested in understanding how they interact at a molecular level. By combining our expertise in modeling and functional studies, we’re working toward a greater depth of understanding in how things function.”

MCH-I is a highly variable group of proteins: they differ from person to person and from species to species. It is one of the “matches” considered for organ transplants. This degree of variability points to evolution driven at least in part by the influence of viruses.

“MCH-I can be very different between individuals. It presents peptide fragments to NK cells, and we think one way NK cells are sensing the virus or the tumor is by recognizing these little peptide fragments,” says Dr. Khakoo.

Research has shown that peptides presented by MHC-I influence how individuals’ bodies react to infections or tumors. “Even so, we haven’t definitively proved that it’s the peptides themselves,” says Dr. Das, who is also an associate professor of Pediatrics at The Ohio State University. “This is because the complexes are so different from one person to the next. That variability could also play a role.”

This is where the modeling work comes in. Mathematical models test hypotheses that are difficult to test experimentally. “You can’t test everything experimentally,” says Dr. Khakoo. “The modeling is essential to narrow hypotheses to provide direction for functional experiments.”

As Drs. Das and Khakoo continue their collaboration, they hope to look at the difference between MCH-I in animal models and in humans.

“Much of our research is done in animal models, and there is a dramatic difference in MCH-I and KIRs from species to species,” says Dr. Das. “We need to understand the differences to know how to apply the research from animal studies to humans.”

Reference:

Das J, Khakoo, SI. NK cells: tuned by peptide? Immunology Reviews. 2015 Sep;267(1):214-227.