Killer cell immunoglobulin-like receptor 3DL1-mediated recognition of human leukocyte antigen B Academic Article uri icon

abstract

  • Members of the killer cell immunoglobulin-like receptor (KIR) family, a large group of polymorphic receptors expressed on natural killer (NK) cells, recognize particular peptide-laden human leukocyte antigen (pHLA) class I molecules and have a pivotal role in innate immune responses. Allelic variation and extensive polymorphism within the three-domain KIR family (KIR3D, domains D0-D1-D2) affects pHLA binding specificity and is linked to the control of viral replication and the treatment outcome of certain haematological malignancies. Here we describe the structure of a human KIR3DL1 receptor bound to HLA-B*5701 complexed with a self-peptide. KIR3DL1 clamped around the carboxy-terminal end of the HLA-B*5701 antigen-binding cleft, resulting in two discontinuous footprints on the pHLA. First, the D0 domain, a distinguishing feature of the KIR3D family, extended towards β2-microglobulin and abutted a region of the HLA molecule with limited polymorphism, thereby acting as an 'innate HLA sensor' domain. Second, whereas the D2-HLA-B*5701 interface exhibited a high degree of complementarity, the D1-pHLA-B*5701 contacts were suboptimal and accommodated a degree of sequence variation both within the peptide and the polymorphic region of the HLA molecule. Although the two-domain KIR (KIR2D) and KIR3DL1 docked similarly onto HLA-C and HLA-B respectively, the corresponding D1-mediated interactions differed markedly, thereby providing insight into the specificity of KIR3DL1 for discrete HLA-A and HLA-B allotypes. Collectively, in association with extensive mutagenesis studies at the KIR3DL1-pHLA-B*5701 interface, we provide a framework for understanding the intricate interplay between peptide variability, KIR3D and HLA polymorphism in determining the specificity requirements of this essential innate interaction that is conserved across primate species.

authors

  • Vivian, Julian P
  • Duncan, Renee C
  • Berry, Richard
  • O’Connor, Geraldine M
  • Reid, Hugh H
  • Beddoe, Travis
  • Gras, Stephanie
  • Saunders, Philippa M
  • Olshina, Maya A
  • Widjaja, Jacqueline ML
  • Harpur, Christopher M
  • Lin, Jie
  • Maloveste, Sebastien M
  • Price, David A
  • Lafont, Bernard AP
  • McVicar, Daniel W
  • Clements, Craig S
  • Brooks, Andrew G
  • Rossjohn, Jamie

publication date

  • November 2011

published in