A Coevolutionary Arms Race between Hosts and Viruses Drives Polymorphism and Polygenicity of NK Cell Receptors

Area of Science:

• Immunology
• Evolutionary Biology
• Computational Biology

Background:

• Natural killer cell receptors (NKRs) detect compromised cells via major histocompatibility class I (MHC-I) and stress molecules.
• The NKR gene family exhibits significant genetic diversity, including gene content and allelic polymorphism, with species-specific expansions.
• The functional significance of NKR gene expansion remains largely unexplained.

Purpose of the Study:

• To investigate the evolutionary drivers behind the expansion and diversification of Natural Killer cell Receptor (NKR) genes.
• To understand the coevolutionary dynamics between host NKRs and viral immune evasion strategies.

Main Methods:

• Development of an agent-based model simulating host-pathogen coevolution.
• Incorporation of viral strategies to downregulate MHC-I expression.
• Analysis of NKR gene evolution under selective pressures.

Main Results:

• Hosts evolved specific inhibitory NKRs targeting particular MHC-I alleles.
• Viruses rapidly evolved MHC-mimicking proteins, even without MHC-I downregulation.
• The NKR locus became polygenic and polymorphic, encoding both inhibitory and activating receptors.

Conclusions:

• NKR gene expansion and polymorphism are driven by coevolution with viruses.
• The evolution of specific inhibitory and activating NKRs enhances host defense against viral threats.
• Agent-based modeling provides insights into the complex interplay between immune receptor evolution and pathogen adaptation.