Members of the Killer Immunoglobulin-Like Receptor (KIR) family, a large group of polymorphic receptors expressed on Natural Killer (NK) cells, recognise particular peptide-laden Human Leukocyte Antigen (pHLA) class I molecules and play a pivotal role in innate immune responses1. 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 malignancies1–3. We describe the structure of the KIR3DL1 receptor, bound to HLA-B*5701 complexed with a self-peptide. KIR3DL1 clamped around the C-terminal end of the HLA-B*5701 antigen (Ag)-binding cleft, resulting in two discontinuous footprints on the pHLA. Firstly, the D0 domain, a distinguishing feature of the KIR3D family, extended towards β2-microglobulin and abutted a region of the HLA molecule that exhibited limited polymorphism, thereby acting as an “innate HLA sensor” domain. Secondly, while the D2-HLA-B*5701 interface exhibited a high degree of complementarity, the D1-pHLA-B*5701 contacts were sub-optimal and accommodated a degree of sequence variation both within the peptide and the polymorphic region of the HLA molecule. While the two-domain KIR (KIR2D) and KIR3DL1 docked similarly onto HLA-C4,5 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.

T cells often alloreact with foreign human leukocyte antigens (HLA). Here we showed the LC13 T cell receptor (TCR), selected for recognition on self-HLA-B( *)0801 bound to a viral peptide, alloreacts with B44 allotypes (HLA-B( *)4402 and HLA-B( *)4405) bound to two different allopeptides. Despite extensive polymorphism between HLA-B( *)0801, HLA-B( *)4402, and HLA-B( *)4405 and the disparate sequences of the viral and allopeptides, the LC13 TCR engaged these peptide-HLA (pHLA) complexes identically, accommodating mimicry of the viral peptide by the allopeptide. The viral and allopeptides adopted similar conformations only after TCR ligation, revealing an induced-fit mechanism of molecular mimicry. The LC13 T cells did not alloreact against HLA-B( *)4403, and the single residue polymorphism between HLA-B( *)4402 and HLA-B( *)4403 affected the plasticity of the allopeptide, revealing that molecular mimicry was associated with TCR specificity. Accordingly, molecular mimicry that is HLA and peptide dependent is a mechanism for human T cell alloreactivity between disparate cognate and allogeneic pHLA complexes.

Rossjohn, Brooks, Vivian, and colleagues provide the most complete picture to date of the impact of KIR3DL1 polymorphism on HLA class I recognition, which can be used to both reevaluate previous work on the involvement of KIR3DL1 in disease as well as inform future disease association studies.

No abstract