title: Increased frequency and function of KIR2DL1-3⁺ NK cells in primary HIV-1 infection are determined by HLA-C group haplotypes.
abstract: The acquisition and maintenance of NK-cell function is mediated by inhibitory killer-cell immunoglobulin-like receptors (KIRs) through their interaction with HLA class I molecules. Recently, HLA-C expression levels were shown to be correlated with protection against multiple outcomes of HIV-1 infection; however, the underlying mechanisms are poorly understood. As HLA-C is the natural ligand for the inhibitory receptors KIR2DL1 and KIR2DL2/3, we sought to determine whether HLA-C group haplotypes affect NK-cell responses during primary HIV-1 infection. The phenotypes and functional capacity of NK cells derived from HIV-1-positive and HIV-1-negative individuals were assessed (N = 42 and N = 40, respectively). HIV-1 infection was associated with an increased frequency of KIR2DL1-3(+) NK cells. Further analysis showed that KIR2DL1(+) NK cells were selectively increased in individuals homozygous for HLA-C2, while HLA-C1-homozygous individuals displayed increased proportions of KIR2DL2/3(+) NK cells. KIR2DL1-3(+) NK cells were furthermore more polyfunctional during primary HIV-1 infection in individuals also encoding for their cognate HLA-C group haplotypes, as measured by degranulation and IFN-γ and TNF-α production. These results identify a novel relationship between HLA-C and KIR2DL(+) NK-cell subsets and demonstrate that HLA-C-mediated licensing modulates NK-cell responses to primary HIV-1 infection.
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Körner
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Granoff
authors.forename: Molly A
authors.initials: MA
authors.lastname: Amero
authors.forename: Michael N
authors.initials: MN
authors.lastname: Sirignano
authors.forename: Sagar A
authors.initials: SA
authors.lastname: Vaidya
authors.forename: Stephanie
authors.initials: S
authors.lastname: Jost
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
authors.forename: Eric S
authors.initials: ES
authors.lastname: Rosenberg
authors.forename: Marcus
authors.initials: M
authors.lastname: Altfeld
mesh_terms: D000328:Adult; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology*; D015236:HLA-C Antigens / Q000235:genetics / Q000276:immunology*; D006239:Haplotypes; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D054342:Receptors, KIR2DL1 / Q000276:immunology; D054343:Receptors, KIR2DL2 / Q000276:immunology; D054344:Receptors, KIR2DL3 / Q000276:immunology
chemical_list: D015236:HLA-C Antigens; C093100:KIR2DL1 protein, human; C515077:KIR2DL2 protein, human; C515078:KIR2DL3 protein, human; D054342:Receptors, KIR2DL1; D054343:Receptors, KIR2DL2; D054344:Receptors, KIR2DL3
keywords: HIV-1; HLA-C; Inhibitory killer-cell immunoglobulin-like receptors (KIRs); Natural killer (NK) cells