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1.
J Immunol ; 206(4): 849-860, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33441440

RESUMO

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


Assuntos
Antígenos HLA-A , Células Matadoras Naturais , Receptores KIR3DL1 , Antígenos HLA-A/química , Antígenos HLA-A/imunologia , Humanos , Células Matadoras Naturais/química , Células Matadoras Naturais/imunologia , Conformação Proteica em alfa-Hélice , Domínios Proteicos , Receptores KIR3DL1/química , Receptores KIR3DL1/imunologia
2.
Proc Natl Acad Sci U S A ; 117(21): 11636-11647, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32404419

RESUMO

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)Ω-2 residues. In HLA-B*57:01, charged PΩ-2 residues were oriented toward the peptide-binding cleft and away from KIR3DL1. In HLA-B*57:03, the charged PΩ-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.


Assuntos
Antígenos de Histocompatibilidade Classe I/genética , Células Matadoras Naturais/fisiologia , Polimorfismo Genético/genética , Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/fisiologia , Humanos , Ativação Linfocitária/genética , Modelos Moleculares , Polimorfismo Genético/fisiologia , Receptores KIR/genética
3.
J Clin Invest ; 128(5): 1903-1912, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29461980

RESUMO

HLA-B*57 control of HIV involves enhanced CD8+ T cell responses against infected cells, but extensive heterogeneity exists in the level of HIV control among B*57+ individuals. Using whole-genome sequencing of untreated B*57+ HIV-1-infected controllers and noncontrollers, we identified a single variant (rs643347A/G) encoding an isoleucine-to-valine substitution at position 47 (I47V) of the inhibitory killer cell immunoglobulin-like receptor KIR3DL1 as the only significant modifier of B*57 protection. The association was replicated in an independent cohort and across multiple outcomes. The modifying effect of I47V was confined to B*57:01 and was not observed for the closely related B*57:03. Positions 2, 47, and 54 tracked one another nearly perfectly, and 2 KIR3DL1 allotypes differing only at these 3 positions showed significant differences in binding B*57:01 tetramers, whereas the protective allotype showed lower binding. Thus, variation in an immune NK cell receptor that binds B*57:01 modifies its protection. These data highlight the exquisite specificity of KIR-HLA interactions in human health and disease.


Assuntos
Variação Genética , Infecções por HIV , HIV-1/imunologia , Antígenos HLA-B , Receptores KIR3DL1 , Adulto , Estudos de Coortes , Feminino , Infecções por HIV/genética , Infecções por HIV/imunologia , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Receptores KIR3DL1/genética , Receptores KIR3DL1/imunologia
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