Student Posters 51st Lorne Proteins Conference 2026

Leukocyte Immunoglobulin-Like Receptor B1 and its interactions with Human Leukocyte Antigens (#345)

Geoff Zhang 1 2 3 4 , James Roest 1 , Julian Vivian 1 3 4 , Chris Langendorf 2 3
  1. Structural Immunobiology, St Vincent’s Institute of Medical Research (SVI), Melbourne, Victoria, Australia
  2. Protein Engineering in Immunity and Metabolism, St Vincent’s Institute of Medical Research (SVI), Melbourne, Victoria, Australia
  3. Department of Medicine, The University of Melbourne , Melbourne, Victoria, Australia
  4. Australian Catholic University, Melbourne, Victoria, Australia

INTRODUCTION: Natural Killer (NK) cells are innate immune cells that form the first line of defence against infections and cancer by using surface receptors to distinguish abnormal or infected cells from healthy ones (1). Many of these receptors recognise human leukocyte antigens (HLAs), molecules found on the surface of healthy cells. There are six HLA genes (HLA-A, -B, -C, -E, -F, and -G), with more than 40,000 allelic variants for HLA-A, -B, and -C within the human population (2). Among the HLA-binding receptors on NK cells is Leukocyte Immunoglobulin-Like Receptor B1 (LILRB1) (2). Unlike many receptors that interact with specific HLA variants, LILRB1 binds to regions of the HLA molecule that remain relatively conserved (3). However, it remains contentious whether this conservation results in equivalent binding across all HLA variants (3). Highlighting the importance of LILRB1 in the immune system, there are a plethora of published antibodies targeting LILRB1.

 AIMS: We aimed to determine whether LILRB1 shows binding preferences for specific HLA types using a Luminex multiplex binding screen with a panel of common HLA variants. We also sought to better understand the molecular basis behind LILRB1’s interactions by solving its structure with X-ray crystallography. Finally, we modelled the interactions between LILRB1 and published monoclonal antibodies using AlphaFold3 to gain insights that could inform future immunotherapeutic applications.

 RESULTS: Here, we found that LILRB1 binds broadly to HLA-A and HLA-C but preferentially binds a subset of HLA-B. We also determined the full-length unbound structure of LILRB1. Structural modelling of antibody interactions shows that most monoclonal antibodies target the regions between domains 1 and 2 or domains 3 and 4 of LILRB1, suggesting the functional importance of these hinge regions. These insights advance our understanding of LILRB1’s binding specificity for HLA and have implications for designing LILRB1-targeting antibody immunotherapies.

  1. [1] Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nature Immunology. 2008 May;9(5):503–10.
  2. [2] Dendrou CA, Petersen J, Rossjohn J, Fugger L. HLA variation and disease. Nature Reviews Immunology. 2018 Jan 2;18(5):325–39.
  3. [3] Wang Q, Song H, Cheng H, Qi J, Nam G, Tan S, et al. Structures of the four Ig-like domain LILRB2 and the four-domain LILRB1 and HLA-G1 complex. Cellular & Molecular Immunology. 2020;17(9):966-75.