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  • Dimorphism in the TCRgamma-chain repertoire defines 2 types of human immunity to Epstein-Barr virus. Blood advances Djaoud, Z., Parham, P. 2020; 4 (7): 1198?1205

    Abstract

    Humans form 2 groups based on their innate immunity to Epstein-Barr virus (EBV). Group 1 makes a strong natural killer (NK)-cell and gammadelta T-cell response, whereas group 2 makes a strong NK-cell response, but a weak gammadelta T-cell response. To investigate the underlying basis for this difference in gammadelta T-cell immunity to EBV, we used next-generation sequencing to compare the gammadelta T-cell receptor (TCR) repertoires of groups 1 and 2. In the absence of EBV, group 1 TCRgamma chains are enriched for complementarity determining region 3 (CDR3s) containing JgammaP, whereas group 2 TCRgamma chains are enriched for CDR3s containing Jgamma2. In group 1 donors, EBV activates many gammadelta T cells expressing Vgamma9JgammaP, inducing proliferation that produces a large population of activated effector cells. The TCRs using Vgamma9JgammaP are closely related to the TCRs of gammadelta T cells that respond to phosphoantigens. In group 2 donors, EBV activates a small subpopulation of gammadelta T cells, most expressing Vgamma9JgammaP. In conclusion, we find that differences in the TCRgamma-chain repertoire underlie the differential response of group 1 and group 2 to EBV.

    View details for DOI 10.1182/bloodadvances.2019001179

    View details for PubMedID 32211881

  • HLAs, TCRs, and KIRs, a Triumvirate of Human Cell-Mediated Immunity. Annual review of biochemistry Djaoud, Z., Parham, P. 2020; 89: 717?39

    Abstract

    In all human cells, human leukocyte antigen (HLA) class I glycoproteins assemble with a peptide and take it to the cell surface for surveillance by lymphocytes. These include natural killer (NK) cells and ?? T cells of innate immunity and ?? T cells of adaptive immunity. In healthy cells, the presented peptides derive from human proteins, to which lymphocytes are tolerant. In pathogen-infected cells, HLA class I expression is perturbed. Reduced HLA class I expression is detected by KIR and CD94:NKG2A receptors of NK cells. Almost any change in peptide presentation can be detected by ?? CD8+ T cells. In responding to extracellular pathogens, HLA class II glycoproteins, expressed by specialized antigen-presenting cells, present peptides to ?? CD4+ T cells. In comparison to the families of major histocompatibility complex (MHC) class I, MHC class II and ?? T cell receptors, the antigenic specificity of the ?? T cell receptors is incompletely understood.

    View details for DOI 10.1146/annurev-biochem-011520-102754

    View details for PubMedID 32569519

  • In vitro education of human natural killer cells by KIR3DL1. Life science alliance Pugh, J., Nemat-Gorgani, N., Djaoud, Z., Guethlein, L. A., Norman, P. J., Parham, P. 2019; 2 (6)

    Abstract

    During development, NK cells are "educated" to respond aggressively to cells with low surface expression of HLA class I, a hallmark of malignant and infected cells. The mechanism of education involves interactions between inhibitory killer immunoglobulin-like receptors (KIRs) and specific HLA epitopes, but the details of this process are unknown. Because of the genetic diversity of HLA class I genes, most people have NK cells that are incompletely educated, representing an untapped source of human immunity. We demonstrate how mature peripheral KIR3DL1+ human NK cells can be educated in vitro. To accomplish this, we trained NK cells expressing the inhibitory KIR3DL1 receptor by co-culturing them with target cells that expressed its ligand, Bw4+HLA-B. After this training, KIR3DL1+ NK cells increased their inflammatory and lytic responses toward target cells lacking Bw4+HLA-B, as though they had been educated in vivo. By varying the conditions of this basic protocol, we provide mechanistic and translational insights into the process NK cell education.

    View details for DOI 10.26508/lsa.201900434

    View details for PubMedID 31723004

  • Two alternate strategies for innate immunity to Epstein-Barr virus: One using NK cells and the other NK cells and ?d T cells. journal of experimental medicine Djaoud, Z., Guethlein, L. A., Horowitz, A., Azzi, T., Nemat-Gorgani, N., Olive, D., Nadal, D., Norman, P. J., Münz, C., Parham, P. 2017; 214 (6): 1827-1841

    Abstract

    Most humans become infected with Epstein-Barr virus (EBV), which then persists for life. Infrequently, EBV infection causes infectious mononucleosis (IM) or Burkitt lymphoma (BL). Type I EBV infection, particularly type I BL, stimulates strong responses of innate immune cells. Humans respond to EBV in two alternative ways. Of 24 individuals studied, 13 made strong NK and ?? T cell responses, whereas 11 made feeble ?? T cell responses but stronger NK cell responses. The difference does not correlate with sex, HLA type, or previous exposure to EBV or cytomegalovirus. Cohorts of EBV(+) children and pediatric IM patients include both group 1 individuals, with high numbers of ?? T cells, and group 2 individuals, with low numbers. The even balance of groups 1 and 2 in the human population points to both forms of innate immune response to EBV having benefit for human survival. Correlating these distinctive responses with the progress of EBV infection might facilitate the management of EBV-mediated disease.

    View details for DOI 10.1084/jem.20161017

    View details for PubMedID 28468758

  • The Intergenic Recombinant HLA-B*46:01 Has a Distinctive Peptidome that Includes KIR2DL3 Ligands. Cell reports Hilton, H. G., McMurtrey, C. P., Han, A. S., Djaoud, Z., Guethlein, L. A., Blokhuis, J. H., Pugh, J. L., Goyos, A., Horowitz, A., Buchli, R., Jackson, K. W., Bardet, W., Bushnell, D. A., Robinson, P. J., Mendoza, J. L., Birnbaum, M. E., Nielsen, M., Garcia, K. C., Hildebrand, W. H., Parham, P. 2017; 19 (7): 1394-1405

    Abstract

    HLA-B(?)46:01 was formed by an intergenic mini-conversion, between HLA-B(?)15:01 and HLA-C(?)01:02, in Southeast Asia during the last 50,000 years, and it has since become the most common HLA-B allele in the region. A functional effect of the mini-conversion was introduction of the C1 epitope into HLA-B(?)46:01, making it an exceptional HLA-B allotype that is recognized by the C1-specific natural killer (NK) cell receptor KIR2DL3. High-resolution mass spectrometry showed that HLA-B(?)46:01 has a low-diversity peptidome that is distinct from those of its parents. A minority (21%) of HLA-B(?)46:01 peptides, with common C-terminal characteristics, form ligands for KIR2DL3. The HLA-B(?)46:01 peptidome is predicted to be enriched for peptide antigens derived from Mycobacterium leprae. Overall, the results indicate that the distinctive peptidome and functions of HLA-B(?)46:01 provide carriers with resistance to leprosy, which drove its rapid rise in frequency in Southeast Asia.

    View details for DOI 10.1016/j.celrep.2017.04.059

    View details for PubMedID 28514659

  • Class I HLA haplotypes form two schools that educate NK cells in different ways. Science immunology Horowitz, A., Djaoud, Z., Nemat-Gorgani, N., Blokhuis, J., Hilton, H. G., Béziat, V., Malmberg, K., Norman, P. J., Guethlein, L. A., Parham, P. 2016; 1 (3)

    Abstract

    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.

    View details for PubMedID 27868107

  • Cytomegalovirus-Infected Primary Endothelial Cells Trigger NKG2C(+) Natural Killer Cells JOURNAL OF INNATE IMMUNITY Djaoud, Z., Riou, R., Gavlovsky, P., Mehlal, S., Bressollette, C., Gerard, N., Gagne, K., Charreau, B., Retiere, C. 2016; 8 (4): 374?85

    Abstract

    Among innate cells, natural killer (NK) cells play a crucial role in the defense against cytomegalovirus (CMV). In some individuals, CMV infection induces the expansion of NKG2C+ NK cells that persist after control of the infection. We have previously shown that KIR2DL+ NK cells, in contrast to NKG2C+ NK cells, contribute to controlling CMV infection using a CMV-infected monocyte-derived dendritic cell (MDDC) model. However, the nature of CMV-infected cells contributing to the expansion of the NKG2C+ NK cell subset remains unclear. To gain more insight into this question, we investigated the contribution of NKG2C+ NK cell activation by CMV-infected primary human aortic endothelial cells (EC) isolated from kidney transplant donors, which constitutively express the human leukocyte antigen (HLA)-E molecule. Here, we show that, although classic HLA class I expression was drastically downregulated, nonclassic HLA-E expression was maintained in CMV-infected EC. By comparing HLA expression patterns in CMV-infected EC, fibroblasts and MDDC, we demonstrate a cell-dependent modulation of HLA-E expression by CMV infection. NKG2C+ NK cell degranulation was significantly triggered by CMV-infected EC regardless of the nature of the HLA-E allele product. EC, predominantly present in vessels, may constitute a privileged site for CMV infection that drives a 'memory' NKG2C+ NK cell subset.

    View details for DOI 10.1159/000445320

    View details for Web of Science ID 000378797300005

    View details for PubMedID 27116381

    View details for PubMedCentralID PMC6738823

  • Large Spectrum of HLA-C Recognition by Killer Ig-like Receptor (KIR)2DL2 and KIR2DL3 and Restricted C1 Specificity of KIR2DS2: Dominant Impact of KIR2DL2/KIR2DS2 on KIR2D NK Cell Repertoire Formation JOURNAL OF IMMUNOLOGY David, G., Djaoud, Z., Willem, C., Legrand, N., Rettman, P., Gagne, K., Cesbron, A., Retiere, C. 2013; 191 (9): 4778?88

    Abstract

    The interactions of killer Ig-like receptor 2D (KIR2D) with HLA-C ligands contribute to functional NK cell education and regulate NK cell functions. Although simple alloreactive rules have been established for inhibitory KIR2DL, those governing activating KIR2DS function are still undefined, and those governing the formation of the KIR2D repertoire are still debated. In this study, we investigated the specificity of KIR2DL1/2/3 and KIR2DS1/2, dissected each KIR2D function, and assessed the impact of revisited specificities on the KIR2D NK cell repertoire formation from a large cohort of 159 KIR and HLA genotyped individuals. We report that KIR2DL2(+) and KIR2DL3(+) NK cells reacted similarly against HLA-C(+) target cells, irrespective of C1 or C2 allele expression. In contrast, KIR2DL1(+) NK cells specifically reacted against C2 alleles, suggesting a larger spectrum of HLA-C recognition by KIR2DL2 and KIR2DL3 than KIR2DL1. KIR2DS2(+) KIR2DL2(-) NK cell clones were C1-reactive irrespective of their HLA-C environment. However, when KIR2DS2 and KIR2DL2 were coexpressed, NK cell inhibition via KIR2DL2 overrode NK cell activation via KIR2DS2. In contrast, KIR2DL1 and KIR2DS2 had an additive enhancing effect on NK cell responses against C1C1 target cells. KIR2DL2/3/S2 NK cells predominated within the KIR repertoire in KIR2DL2/S2(+) individuals. In contrast, the KIR2DL1/S1 NK cell compartment is dominant in C2C2 KIR2DL2/S2(-) individuals. Moreover, our results suggest that together with KIR2DL2, activating KIR2DS1 and KIR2DS2 expression limits KIR2DL1 acquisition on NK cells. Altogether, our results suggest that the NK cell repertoire is remolded by the activating and inhibitory KIR2D and their cognate ligands.

    View details for DOI 10.4049/jimmunol.1301580

    View details for Web of Science ID 000325929000035

    View details for PubMedID 24078689

  • Amplified NKG2C(+) NK Cells in Cytomegalovirus (CMV) Infection Preferentially Express Killer Cell Ig-like Receptor 2DL: Functional Impact in Controlling CMV-Infected Dendritic Cells JOURNAL OF IMMUNOLOGY Djaoud, Z., David, G., Bressollette, C., Willem, C., Rettman, P., Gagne, K., Legrand, N., Mehlal, S., Cesbron, A., Imbert-Marcille, B., Retiere, C. 2013; 191 (5): 2708?16

    Abstract

    CMV infection represents a major complication in hematopoietic stem cell transplantation, which compromises graft outcome. Downregulation of HLA class I expression is one mechanism by which CMV evades T cell-mediated immune detection, rendering infected cells vulnerable to killer cell Ig-like receptor (KIR)(+) NK cells. In this study, we observed that the amplified NKG2C(+) NK cell population observed specifically in CMV seropositive individuals mainly expressed KIR2DL receptors. We have shown that HLA class I expression was downregulated on CMV-infected immature dendritic cells (iDCs), which escape to HLA-A2-pp65-specific T lymphocytes but strongly trigger the degranulation of KIR2D(+) NK cells. CMV infection conferred a vulnerability of C2C2(+) iDCs to educated KIR2DL1(+) and KIR2DL3(+) NK cell subsets. Alloreactivity of KIR2DL1(+) NK cell subsets against C1C1(+) iDCs was maintained independently of CMV infection. Unexpectedly, CMV-infected C1C1(+) iDCs did not activate KIR2DL3(+) NK cell reactivity, suggesting a potential CMV evasion to KIR2DL3 NK cell recognition. Altogether, the coexpression of KIR and NKG2C on expanded NK cell subsets could be related to a functional contribution of KIR in CMV infection and should be investigated in hematopoietic stem cell transplantation, in which the beneficial impact of CMV infection has been reported on the graft-versus-leukemia effect.

    View details for DOI 10.4049/jimmunol.1301138

    View details for Web of Science ID 000323393300071

    View details for PubMedID 23918974

  • Both the nature of KIR3DL1 alleles and the KIR3DL1/S1 allele combination affect the KIR3DL1 NK-cell repertoire in the French population EUROPEAN JOURNAL OF IMMUNOLOGY Gagne, K., Willem, C., Legrand, N., Djaoud, Z., David, G., Rettman, P., Bressollette-Bodin, C., Senitzer, D., Esbelin, J., Cesbron-Gautier, A., Schneider, T., Retiere, C. 2013; 43 (4): 1085?98

    Abstract

    NK-cell functions are regulated by many activating and inhibitory receptors including KIR3DL1. Extensive allelic polymorphism and variability in expression can directly alter NK-cell phenotype and functions. Here we investigated the KIR3DL1(+) NK-cell repertoire, taking into account the allelic KIR3DL1/S1 polymorphism, KIR3DL1 phenotype, and function. All 109 studied individuals possessed at least one KIR3DL1 allele, with weak KIR3DL1*054, or null alleles being frequently present. In KIR3DL1(high/null) individuals, we observed a bimodal distribution of KIR3DL1(+) NK cells identified by a different KIR3DL1 expression level and cell frequency regardless of a similar amount of both KIR3DL1 transcripts, HLA background, or KIR2D expression. However, this bimodal distribution can be explained by a functional selection following a hierarchy of KIR3DL1 receptors. The higher expression of KIR3DL1 observed on cord blood NK cells suggests the expression of the functional KIR3DL1*004 receptors. Thus, the low amplification of KIR3DL1(high) , KIR3DL1*004 NK-cell subsets during development may be due to extensive signaling via these two receptors. Albeit in a nonexclusive manner, individual immunological experience may contribute to shaping the KIR3DL1 NK-cell repertoire. Together, this study provides new insight into the mechanisms regulating the KIR3DL1 NK-cell repertoire.

    View details for DOI 10.1002/eji.201243007

    View details for Web of Science ID 000317859200025

    View details for PubMedID 23436464

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