Dependency of Ly49 Recognition on Anchor Residues of Peptide Bound to MHC-I

Elsa A Marquez
In rodents, Ly49s are prominent natural killer (NK) cell receptors that interact with peptide-bound class I major histocompatibility complex (MHC-I). This association generally induces inhibitory signals when MHC-I presents self-peptides, thus blocking NK cell activation against healthy cells. Inhibitory Ly49 receptors can be peptide selective in their recognition of MHC-I-peptide complexes, affording them a level of discrimination beyond detecting the presence or absence of specific MHC-I
more » ... specific MHC-I allele products. NK cell inhibitory Ly49s associate with MHC-I at a region under the MHC-I peptide binding groove, without direct contact with the peptide bound; however, specific details of peptide dependent Ly49 recognition have not been fully explored. The mouse NK cell receptor Ly49C recognize its MHC-I ligand H-2K b in a peptide selective and specific fashion. However, the molecular basis for Ly49C peptide specific recognition of H-2K b has not been fully elucidated. Utilizing functional assays, we demonstrated that both the auxiliary anchor residue at position 3 (P3) and the adjacent residue at position 2 (P2), that also anchors into the peptide binding groove, influence Ly49C peptide selectivity in recognition of H-2K b . In particular, we found that the Ly49C and H-2K b interaction is supported by non-polar aliphatic residues at P3 and bulky non-polar aliphatic residues at P2. Previous studies in our laboratory also showed the importance of peptide anchor residues in determining recognition between a rat Ly49 receptor, Ly49i2, and its cognate ligand RT1-A1 c . This suggests that peptide anchor residues bound to MHC-I may be modulators of Ly49 peptide specificity in rodent models of Ly49 and MHC-I interaction. iii In addition, we used functional assays to demonstrate peptide-dependent antagonism of mouse NK cell inhibition using as a model Ly49C and H-2K b association. Partial NK cell antagonism, in other words partial depression of inhibition, was observed during the co-presentation of peptide-MHC-I (pMHC-I) complexes that support Ly49C-H-2K b interaction and pMHC-I complexes that can bind Ly49C at an intermediate level. In contrast, a weaker antagonistic phenotype was observed by co-expression of pMHC-I complexes that confer H-2K b and Ly49C interaction together with pMHC-I complexes that bind Ly49C at low to null levels. Collectively, our studies show that peptides bound to H-2K b are fundamental in the integration of NK cell signaling events that determine NK activity. Rodent Ly49 receptors can play an important role in NK cell function for the clearance of tumorigenic cells as well as virally infected cells. Given that the peptide repertoire within a cell is subjected to modifications during cell stress, such as tumorigenesis or viral infection, it is of importance to understand how Ly49 directed NK cell function is affected by the nature of the peptides bound to MHC-I. iv
doi:10.7939/r3x34n08h fatcat:c23uxohryjd7tiixpsl3jwzupq