Article

NK Cell Tolerance of Self-Specific Activating Receptor KIR2DS1 in Individuals with Cognate HLA-C2 Ligand

Immunology Program, Sloan-Kettering Institute for Cancer Research, New York, NY 10065
The Journal of Immunology (Impact Factor: 5.36). 04/2013; 190(9). DOI: 10.4049/jimmunol.1202120
Source: PubMed

ABSTRACT NK cells are regulated by inhibiting and activating cell surface receptors. Most inhibitory receptors recognize MHC class I Ags and protect healthy cells from NK cell-mediated autoaggression. However, certain activating receptors, including the human activating killer cell Ig-like receptor (KIR) 2DS1, also recognize MHC class I. This fact raises the question of how NK cells expressing such activating receptors are tolerized to host tissues. We investigated whether the presence of HLA-C2, the cognate ligand for 2DS1, induces tolerance in 2DS1-expressing NK cells. Anti-HLA-C2 activity could be detected in vitro in some 2DS1 positive NK clones irrespective of the presence or absence of HLA-C2 ligand in the donor. The frequency of anti-HLA-C2 reactivity was high in donors homozygous for HLA-C1. Surprisingly, no significant difference was seen in the frequency of anti-HLA-C2 cytotoxicity in donors heterozygous for HLA-C2 and donors without HLA-C2 ligand. However, donors homozygous for HLA-C2, compared with all other donors, had significantly reduced frequency of anti-HLA-C2 reactive clones. The 2DS1 positive clones that express inhibitory KIR for self-HLA class I were commonly noncytotoxic, and anti-HLA-C2 cytotoxicity was nearly exclusively restricted to 2DS1 single positive clones lacking inhibitory KIR. 2DS1 single positive NK clones with anti-HLA-C2 reactivity were also present posttransplantation in HLA-C2 positive recipients of hematopoietic stem cell transplants from 2DS1 positive donors. These results demonstrate that many NK cells with anti-HLA-C2 reactivity are present in HLA-C1 homozygous and heterozygous donors with 2DS1. In contrast, 2DS1 positive clones from HLA-C2 homozygous donors are frequently tolerant to HLA-C2.

1 Follower
 · 
64 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background:Conflicting results have been reported regarding the predicative roles of alloreactive natural killer (NK) cells on the outcomes of transplantation in leukaemia patients.Methods:We prospectively analysed the human leukocyte antigen (HLA) typing of donor-recipient pairs and the KIR typing of the donors in 97 CML patients to address the predictive roles of NK cells in relapse undergoing T-cell-replete haploidentical transplantation.Results:Patients with class I ligands for the donor-inhibitory KIR gene exhibited decreased molecular and haematologic relapse rates (P=0.003 and P=0.015, respectively). There was a significantly reduced risk of molecular and haematologic relapse in patients with HLA-C1C2 or C2C2 who accepted donors with KIR2DS1 or in patients with HLA-Bw4 who accepted donors with KIR3DS1 ('recipient with relevant KIR ligand for donor-activating KIR', n=25), compared with the remaining transplants (n=72, P=0.009 and P=0.009, respectively). In addition, the presence of class I ligand in the recipients of donor-activating KIR contributed to a decreased relapse rate in patients lacking class I ligand in the recipient of donor-inhibitory KIR (P=0.04 and P=0.03, respectively).Conclusions:This study suggests that the presence of class I ligands for the donor-activating or donor-inhibitory KIR gene in the recipient might confer some protection against leukaemic relapse in T-cell-replete haploidentical transplantation.British Journal of Cancer advance online publication 31 July 2014; 1 doi:10.1038/bjc.2014.423 www.bjcancer.com.
    British Journal of Cancer 07/2014; 111(6). DOI:10.1038/bjc.2014.423 · 4.82 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose Not all natural killer (NK) cells are equally cytotoxic against leukemia because of differences in receptor gene content and surface expression. We correlated NK cell genotype and phenotype at diagnosis of childhood acute lymphoblastic leukemia (ALL) with minimal residual disease (MRD) after induction chemotherapy. Experimental Design The NK cells and leukemia blasts of 244 patients were analyzed at diagnosis by killer-cell immunoglobulin-like receptor (KIR) typing and immunophenotyping. The results were correlated statistically to post-induction MRD status. Results The odds of being MRD positive in patients with KIR telomeric (Tel)-A/B genotype was 2.85 times the odds in those with Tel-A/A genotype (p=0.035). MRD positive patients were more likely to have KIR2DL5A (p=0.006) and expressed less activating receptor NKp46 and FASL on their NK cells (p=0.0074 and p=0.029, respectively). The odds of being MRD positive increased by 2.01-fold for every percentage increase in NK cells expressing KIR2DL1 in the presence of HLA-C2 ligand (p=0.034). The quantity of granzyme B inhibitor PI-9 in the leukemia blasts was greater in patients who were MRD positive (p=0.038). Collectively, five NK cell-related factors (Tel-B associated KIR2DL5A, NKp46, FASL, Granzyme B, and PI-9) are strongly associated with MRD positivity at the end of induction with 100% sensitivity and 80% specificity. Conclusions Our data support the hypothesis that NK cells with a strong effector phenotype in the setting of decreased leukemia resistance are associated with better leukemia control.
    Clinical Cancer Research 10/2014; 20(23). DOI:10.1158/1078-0432.CCR-14-0479 · 8.19 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This paper shows the transient behavior of a system which boosts a part of the battery voltage for a electric vehicle. This system consists of the powertrain of electric vehicles and a bi-directional isolated DC-DC converter called dual active bridge (DAB). This system can compensate the battery voltage drops with high efficiency compared with the conventional series chopper system. In many studies, the DAB converter operates in the steady state. On the other hand, this paper analyzes the operation of the DAB converter in the transient state. Especially, the operation at the start of the DAB converter is focused on.
    2014 International Power Electronics Conference (IPEC-Hiroshima 2014 ECCE-ASIA); 05/2014