PMID- 32404419 OWN - NLM STAT- MEDLINE DCOM- 20200818 LR - 20201113 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 117 IP - 21 DP - 2020 May 26 TI - The molecular basis of how buried human leukocyte antigen polymorphism modulates natural killer cell function. PG - 11636-11647 LID - 10.1073/pnas.1920570117 [doi] AB - Micropolymorphisms within human leukocyte antigen (HLA) class I molecules can change the architecture of the peptide-binding cleft, leading to differences in peptide presentation and T cell recognition. The impact of such HLA variation on natural killer (NK) cell recognition remains unclear. Given the differential association of HLA-B*57:01 and HLA-B*57:03 with the control of HIV, recognition of these HLA-B57 allomorphs by the killer cell immunoglobulin-like receptor (KIR) 3DL1 was compared. Despite differing by only two polymorphic residues, both buried within the peptide-binding cleft, HLA-B*57:01 more potently inhibited NK cell activation. Direct-binding studies showed KIR3DL1 to preferentially recognize HLA-B*57:01, particularly when presenting peptides with positively charged position (P)Omega-2 residues. In HLA-B*57:01, charged POmega-2 residues were oriented toward the peptide-binding cleft and away from KIR3DL1. In HLA-B*57:03, the charged POmega-2 residues protruded out from the cleft and directly impacted KIR3DL1 engagement. Accordingly, KIR3DL1 recognition of HLA class I ligands is modulated by both the peptide sequence and conformation, as determined by the HLA polymorphic framework, providing a rationale for understanding differences in clinical associations. FAU - Saunders, Philippa M AU - Saunders PM AD - Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3010, Australia. FAU - MacLachlan, Bruce J AU - MacLachlan BJ AUID- ORCID: 0000-0002-2685-2733 AD - Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. AD - Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia. FAU - Pymm, Phillip AU - Pymm P AD - Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. AD - Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia. AD - Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia. FAU - Illing, Patricia T AU - Illing PT AUID- ORCID: 0000-0002-3870-0796 AD - Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. AD - Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia. FAU - Deng, Yuanchen AU - Deng Y AD - Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3010, Australia. FAU - Wong, Shu Cheng AU - Wong SC AD - Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3010, Australia. FAU - Oates, Clare V L AU - Oates CVL AD - Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3010, Australia. FAU - Purcell, Anthony W AU - Purcell AW AUID- ORCID: 0000-0003-0532-8331 AD - Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. AD - Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia. FAU - Rossjohn, Jamie AU - Rossjohn J AUID- ORCID: 0000-0002-2020-7522 AD - Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; jamie.rossjohn@monash.edu julian.vivian@monash.edu agbrooks@unimelb.edu.au. AD - Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia. AD - Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia. AD - Institute of Infection and Immunity, School of Medicine, Cardiff University, CF14 4XN Cardiff, United Kingdom. FAU - Vivian, Julian P AU - Vivian JP AUID- ORCID: 0000-0002-9400-4437 AD - Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; jamie.rossjohn@monash.edu julian.vivian@monash.edu agbrooks@unimelb.edu.au. AD - Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia. AD - Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia. FAU - Brooks, Andrew G AU - Brooks AG AUID- ORCID: 0000-0002-4085-9683 AD - Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3010, Australia; jamie.rossjohn@monash.edu julian.vivian@monash.edu agbrooks@unimelb.edu.au. LA - eng SI - PDB/6V2O SI - PDB/6V2P SI - PDB/6V2Q SI - PDB/6V3J PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200513 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Histocompatibility Antigens Class I) RN - 0 (Receptors, KIR) SB - IM MH - Histocompatibility Antigens Class I/chemistry/*genetics/physiology MH - Humans MH - Killer Cells, Natural/*physiology MH - Lymphocyte Activation/genetics MH - Models, Molecular MH - Polymorphism, Genetic/*genetics/physiology MH - Receptors, KIR/genetics PMC - PMC7261055 OTO - NOTNLM OT - HLA OT - KIR OT - natural killer cells COIS- The authors declare no competing interest. EDAT- 2020/05/15 06:00 MHDA- 2020/08/19 06:00 PMCR- 2020/11/13 CRDT- 2020/05/15 06:00 PHST- 2020/05/15 06:00 [pubmed] PHST- 2020/08/19 06:00 [medline] PHST- 2020/05/15 06:00 [entrez] PHST- 2020/11/13 00:00 [pmc-release] AID - 1920570117 [pii] AID - 201920570 [pii] AID - 10.1073/pnas.1920570117 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2020 May 26;117(21):11636-11647. doi: 10.1073/pnas.1920570117. Epub 2020 May 13.