The Role of the HLA Class I α2 Helix in Determining Ligand Hierarchy for the Killer Cell Ig-like Receptor 3DL1

Abstract HLA class I molecules that represent ligands for the inhibitory killer cell Ig-like receptor (KIR) 3DL1 found on NK cells are categorically defined as those HLA-A and HLA-B allotypes containing Bw4 motif, yet KIR3DL1 demonstrates hierarchical recognition of these HLA-Bw4 ligands. To better understand molecular basis underpinning differential recognition, HLA-ABw4 family were investigated. Transfected human 721.221 expressing HLA-A*32:01 strongly inhibited primary KIR3DL1+ cells, whereas HLA-A*24:02 HLA-A*23:01 displayed intermediate potency HLA-A*25:01 failed to inhibit activation cells. Structural studies demonstrated by used identical contacts potent HLA-B*57:01 ligand. Namely, D1–D2 domains placed over α1 helix α2 binding cleft, respectively, D0 domain contacted side molecule. Nevertheless, functional analyses showed was more sensitive substitutions within HLA-A*24:02, including residues Ile142 Lys144. Furthermore, presence Thr149 in abrogated inhibition. Together, data demonstrate a role determining hierarchy Thus, is dependent complex interplay between peptide repertoire, polymorphisms proximal helix. Collectively, furthers our understanding will inform genetic association immunogenetics examining disease settings.