Dimorphic HLA-B signal peptides differentially influence HLA-E- and natural killer cell-mediated cytolysis of HIV-1-infected target cells

Merino, Aimee; Sabbaj, Steffanie; Easlick, Juliet; Goepfert, Paul; Kaslow, Richard A.; Tang, Jianming

doi:10.1111/cei.12187

Cited by 32 publications

(45 citation statements)

References 41 publications

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“…It seems likely that both processes act in synergy to build functional potential in the NKG2A + NK cell subset, similar to what has been observed for KIR-mediated education in self KIR + CD57 + NK cells (19). Notably, the strength of the NKG2A-HLA-E interaction is determined by dimorphism in the HLA-E leader sequence peptide at position 2 (P2) (methionine versus threonine) and significantly influences the missing self response of NKG2A + NK cells (24,25). The link between inhibitory receptor input (through NKG2A) and function suggests that education plays an important role in shaping the responsiveness of the NKG2A + NK cell subset.…”

Section: Nkg2asupporting

confidence: 54%

Microchip-Based Single-Cell Imaging Reveals That CD56dimCD57−KIR−NKG2A+ NK Cells Have More Dynamic Migration Associated with Increased Target Cell Conjugation and Probability of Killing Compared to CD56dimCD57−KIR−NKG2A− NK Cells

Forslund

Sohlberg

Enqvist

et al. 2015

The Journal of Immunology

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NK cells are functionally educated by self-MHC specific receptors, including the inhibitory killer cell Ig-like receptors (KIRs) and the lectin-like CD94/NKG2A heterodimer. Little is known about how NK cell education influences qualitative aspects of cytotoxicity such as migration behavior and efficacy of activation and killing at the single-cell level. In this study, we have compared the behavior of FACS-sorted CD56dimCD57−KIR−NKG2A+ (NKG2A+) and CD56dimCD57−KIR−NKG2A− (lacking inhibitory receptors; IR−) human NK cells by quantifying migration, cytotoxicity, and contact dynamics using microchip-based live cell imaging. NKG2A+ NK cells displayed a more dynamic migration behavior and made more contacts with target cells than IR− NK cells. NKG2A+ NK cells also more frequently killed the target cells once a conjugate had been formed. NK cells with serial killing capacity were primarily found among NKG2A+ NK cells. Conjugates involving IR− NK cells were generally more short-lived and IR− NK cells did not become activated to the same extent as NKG2A+ NK cells when in contact with target cells, as evident by their reduced spreading response. In contrast, NKG2A+ and IR− NK cells showed similar dynamics in terms of duration of conjugation periods and NK cell spreading response in conjugates that led to killing. Taken together, these observations suggest that the high killing capacity of NKG2A+ NK cells is linked to processes regulating events in the recognition phase of NK–target cell contact rather than events after cytotoxicity has been triggered.

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Section: Nkg2asupporting

confidence: 54%

Microchip-Based Single-Cell Imaging Reveals That CD56dimCD57−KIR−NKG2A+ NK Cells Have More Dynamic Migration Associated with Increased Target Cell Conjugation and Probability of Killing Compared to CD56dimCD57−KIR−NKG2A− NK Cells

Forslund

Sohlberg

Enqvist

et al. 2015

The Journal of Immunology

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“…Furthermore, positions 67 and 116 (and to a lesser extent position 97) of the HLA-B antigen-binding groove are critical determinants of the binding specificity of some HLA-B alleles for KIR3DL1 or KIR3DS1 receptors (22). Beyond the MHC-I antigen-binding groove, we identified an association between BD and a variant of the HLA-B signal peptide that independently regulates CTL and NK-cell activation through HLA-E and the C-type lectin-like heterodimeric receptors, CD94/NKG2 (34)(35)(36). Coincidentally, we previously have identified an association between BD and KLCR4, which encodes the C-type lectin-like receptor, NKG2F (6).…”

Section: Discussionmentioning

confidence: 93%

Behçet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity

Ombrello

Kirino

Bakker

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

124

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The HLA protein, HLA-B*51, encoded by HLA-B in MHC, is the strongest known genetic risk factor for Behçet disease (BD). Associations between BD and other factors within the MHC have been reported also, although strong regional linkage disequilibrium complicates their confident disentanglement from HLA-B*51. In the current study, we examined a combination of directly obtained and imputed MHC-region SNPs, directly obtained HLA-B locus types, and imputed classical HLA types with their corresponding polymorphic amino acid residues for association with BD in 1,190 cases and 1,257 controls. SNP mapping with logistic regression of the MHC identified the HLA-B/MICA region and the region between HLA-F and HLA-A as independently associated with BD (P < 1.7 × 10 −8 ). HLA-B*51, -A*03, -B*15, -B*27, -B*49, -B*57, and -A*26 each contributed independently to BD risk. We directly examined rs116799036, a noncoding SNP upstream of HLA-B that was recently suggested to underlie the association of HLA-B*51 with BD, but we were unable to replicate that finding in our collection. Instead, we mapped the BD association to seven MHC class I (MHC-I) amino acid residues, including anchor residues that critically define the selection and binding of peptides to MHC-I molecules, residues known to influence MHC-Ikiller immunoglobulin-like receptor interactions, and a residue located in the signal peptide of HLA-B. The locations of these variants collectively implicate MHC-I peptide binding in the pathophysiology of BD. Furthermore, several lines of evidence suggest a role for altered regulation of cellular cytotoxicity in BD pathogenesis.HLA imputation | autoinflammation | antigen presentation | killer immunoglobulin-like receptors | natural killer cells

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“…Uninfected partners of T/T genotype were more resistant to infection, than uninfected partners of either M/T or M/M genotype. Moreover, the NKG2A + NK cells from uninfected T/T partners were more effective at killing autologous HIV-infected target cells in vitro , than the NKG2A + NK cells of uninfected M/T or M/M partners (7, 8). Here the effect of -21M is dominant and -21T is subordinate, the hierarchy observed throughout our analysis.…”

Section: Discussionmentioning

confidence: 95%

“…Subsequent appreciation that Bw4 correlates with -21T HLA-B led to a reanalysis of the clinical data which showed that the beneficial effects correlate well with -21T HLA-B homozygosity (9). Thus the correlation with Bw4 homozygosity can also be interpreted in terms of a mechanism involving HLA-E recognition by the CD56 dim CD94:NKG2A + cells of T/T donors, NK cells known to be effective against HIV (7, 8). Thus the protection associated with Bw4 + HLA-B homozygosity could be mediated by KIR3DL1 + cells or CD94:NKG2A + cells, or by their combination.…”

Section: Discussionmentioning

confidence: 99%

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Class I HLA haplotypes form two schools that educate NK cells in different ways

et al. 2016

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Summary Natural killer (NK) cells are lymphocytes having vital functions in innate and adaptive immunity, as well as placental reproduction. Controlling education and functional activity of human NK cells are various receptors that recognize HLA class I on the surface of tissue cells. Epitopes of polymorphic HLA-A,-B and –C are recognized by equally diverse killer cell immunoglobulin-like receptors (KIR). In addition, a peptide cleaved from the leader sequence of HLA-A,-B or –C must bind to HLA-E for it to become a ligand for the conserved CD94:NKG2A receptor. Methionine/threonine dimorphism at position -21 of the leader sequence divides HLA-B allotypes into a majority having -21T that do not supply HLA-E binding peptides and a minority having -21M, that do. Genetic analysis of human populations worldwide shows how haplotypes with -21M HLA-B rarely encode the KIR ligands: Bw4+HLA-B and C2+HLA-C KIR. Thus there are two fundamental forms of HLA haplotype: one preferentially supplying CD94:NKG2A ligands, the other preferentially supplying KIR ligands. -21 HLA-B dimorphism divides the human population into three groups: M/M, M/T and T/T. Mass cytometry and assays of immune function, shows how M/M and M/T individuals have CD94:NKG2A+ NK cells which are better educated, phenotypically more diverse and functionally more potent than those in T/T individuals. Fundamental new insights are given to genetic control of NK cell immunity and the evolution that has limited the number of NK cell receptor ligands encoded by an HLA haplotype. These finding suggest new ways to dissect the numerous clinical associations with HLA class I.

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Dimorphic HLA-B signal peptides differentially influence HLA-E- and natural killer cell-mediated cytolysis of HIV-1-infected target cells

Cited by 32 publications

References 41 publications

Microchip-Based Single-Cell Imaging Reveals That CD56dimCD57−KIR−NKG2A+ NK Cells Have More Dynamic Migration Associated with Increased Target Cell Conjugation and Probability of Killing Compared to CD56dimCD57−KIR−NKG2A− NK Cells

Microchip-Based Single-Cell Imaging Reveals That CD56dimCD57−KIR−NKG2A+ NK Cells Have More Dynamic Migration Associated with Increased Target Cell Conjugation and Probability of Killing Compared to CD56dimCD57−KIR−NKG2A− NK Cells

Behçet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity

Class I HLA haplotypes form two schools that educate NK cells in different ways

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