A license to kill: The evolution of NK cell receptors

Abstract

Natural killer (NK) cells innate immune cells that play a crucial role against viral infections and tumors. To be tolerant against healthy tissue and simultaneously attack infected cells, the activity of NK cells must be tightly regulated. Unlike B and T cells, NK cell do not undergo DNA rearrangements to generate a diverse repertoire of cell surface receptors. Instead, NK cells use a sophisticated array of germline-encoded activating and inhibiting receptors. The best characterized mechanism of NK cell activation is “missing self” detection, i.e. the recognition of virally infected or transformed cells that reduce their MHC expression to evade cytotoxic T cells. To monitor the expression of MHC-I on target cells, NK cells have monomorphic inhibitory receptors which interact with conserved MHC molecules. However, there are other NK cell receptors (NKRs) encoded by gene families showing a remarkable genetic diversity. Thus, NKR haplotypes contain several genes encoding for receptors with activating and inhibiting signaling, and that vary in gene content and allelic polymorphism. But if missing-self detection can be achieved by a monomorphic NKR system why have these polygenic and polymorphic receptors evolved? In this thesis, we use computational evolutionary modelling, data analysis, and mathematical modelling to answer the question of why NK cell receptors have evolved to become specific, polygenic, and polymorphic. We propose that NKRs might have possibly diversified due to the selection pressure imposed by the successful immunoevasive mechanisms evolved by several pathogens. We focus on different hypotheses related to viral evasion mechanisms, i.e. we study the effects of viral evolution of MHC-decoys, and selective MHC down-regulation on the evolution of NK cell receptors. Additionally, we study whether NKRs should diversify to be able to detect peptides of viral origin presented on MHC molecules. We find that NK cell receptors evolve to become specific to distinguish self from non-self and that the required specificity selects for the evolution of polygenicity and polymorphism. The degree of the evolved genetic diversity varies depending on the viral strategy used to escape the NK cell response. While our studies suggest that selective MHC downregulation and peptide sensitivity can drive the evolution of polygenic haplotypes encoding NK cell receptors, the highest genetic diversity evolves in host populations infected with viruses that readily evolve MHC-like decoys. The results in this thesis shed light on the evolutionary processes of NK cell receptors, providing plausible explanations for this fascinating complex system.