The Experts below are selected from a list of 13389 Experts worldwide ranked by ideXlab platform
Miguel Lopezbotet - One of the best experts on this subject based on the ideXlab platform.
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analysis of memory like natural killer cells in human cytomegalovirus infected children undergoing αβ t and b cell depleted hematopoietic stem cell transplantation for hematological malignancies
Haematologica, 2016Co-Authors: Letizia Muccio, Miguel Lopezbotet, Michela Falco, Alice Bertaina, Franco Locatelli, Lorenzo Moretta, Alessandro Moretta, Daniela Pende, Raffaella Meazza, Mariella Della ChiesaAbstract:We analyzed the impact of human cytomegalovirus infection on the development of natural killer cells in 27 pediatric patients affected by hematological malignancies, who had received a HLA-haploidentical hematopoietic stem cell transplantation, depleted of both α/β+ T cells and B cells. In line with previous studies in adult recipients of umbilical cord blood transplantation, we found that human cytomegalovirus reactivation accelerated the emergence of mature natural killer cells. Thus, most children displayed a progressive expansion of a memory-like natural killer cell subset expressing NKG2C, a putative receptor for human cytomegalovirus, and CD57, a marker of terminal natural killer cell differentiation. NKG2C+CD57+ natural killer cells were detectable by month 3 following hematopoietic stem cell transplantation and expanded until at least month 12. These cells were characterized by high killer Ig-like receptors (KIRs) and leukocyte inhibitory receptor 1 (LIR-1) and low Siglec-7, NKG2A and Interleukin-18Rα expression, killed tumor targets and responded to cells expressing HLA-E (a NKG2C ligand). In addition, they were poor Interferon-γ producers in response to Interleukin-12 and Interleukin-18. The impaired response to these cytokines, together with their highly differentiated profile, may reflect their skewing toward an adaptive condition specialized in controlling human cytomegalovirus. In conclusion, in pediatric patients receiving a type of allograft different from umbilical cord blood transplantation, human cytomegalovirus also induced memory-like natural killer cells, possibly contributing to controlling infections and reinforcing anti-leukemia effects.
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antibody mediated response of NKG2cbright nk cells against human cytomegalovirus
Journal of Immunology, 2015Co-Authors: Marcel Costagarcia, Carlos Vilches, Miguel Lopezbotet, Andrea Vera, Manuela Moraru, Aura MuntasellAbstract:Human CMV (HCMV) infection promotes a variable and persistent expansion of functionally mature NKG2C(bright) NK cells. We analyzed NKG2C(bright) NK cell responses triggered by Abs from HCMV(+) sera against HCMV-infected MRC5 fibroblasts. Specific Abs promoted the degranulation (i.e., CD107a expression) and the production of cytokines (TNF-α and IFN-γ) by a significant fraction of NK cells, exceeding the low natural cytotoxicity against HCMV-infected targets. NK cell-mediated Ab-dependent cell-mediated cytotoxicity was limited by viral Ag availability and HLA class I expression on infected cells early postinfection and increased at late stages, overcoming viral immunoevasion strategies. Moreover, the presence of specific IgG triggered the activation of NK cells against Ab-opsonized cell-free HCMV virions. As compared with NKG2A(+) NK cells, a significant proportion of NKG2C(bright) NK cells was FceR γ-chain defective and highly responsive to Ab-driven activation, being particularly efficient in the production of antiviral cytokines, mainly TNF-α. Remarkably, the expansion of NKG2C(bright) NK cells in HCMV(+) subjects was related to the overall magnitude of TNF-α and IFN-γ cytokine secretion upon Ab-dependent and -independent activation. We show the power and sensitivity of the anti-HCMV response resulting from the cooperation between specific Abs and the NKG2C(bright) NK-cell subset. Furthermore, we disclose the proinflammatory potential of NKG2C(bright) NK cells, a variable that could influence the individual responses to other pathogens and tumors.
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expansion of cd94 NKG2c nk cells in response to human cytomegalovirus infected fibroblasts
Blood, 2006Co-Authors: Monica Guma, Ana Angulo, Matthias Budt, Andrea Saez, Tamara Brckalo, Hartmut Hengel, Miguel LopezbotetAbstract:CD94/NKG2C+ natural killer (NK) cells are increased in healthy individuals infected with human cytomegalovirus (HCMV), suggesting that HCMV infection may shape the NK cell receptor repertoire. To address this question, we analyzed the distribution of NK cell subsets in peripheral blood lymphocytes (PBLs) cocultured with HCMV-infected fibroblasts. A substantial increase of NK cells was detected by day 10 in samples from a group of HCMV+ donors, and CD94/NKG2C+ cells outnumbered the CD94/NKG2A+ subset. Fibroblast infection was required to induce the preferential expansion of CD94/NKG2C+ NK cells that was comparable with allogeneic or autologous fibroblasts, and different virus strains. A CD94-specific monoclonal antibody (mAb) abrogated the effect, supporting an involvement of the lectinlike receptor. Purified CD56+ populations stimulated with HCMV-infected cells did not proliferate, but the expansion of the CD94/NKG2C+ subset was detected in the presence of interleukin-15 (IL-15). Experiments with HCMV deletion mutants indicated that the response of CD94/NKG2C+ NK cells was independent of the UL16, UL18, and UL40 HCMV genes, but was impaired when cells were infected with a mutant lacking the US2-11 gene region. Taken together the data support that the interaction of CD94/NKG2C with HCMV-infected fibroblasts, concomitant to the inhibition of human leukocyte antigen (HLA) class I expression, promotes an outgrowth of CD94/NKG2C+ NK cells.
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imprint of human cytomegalovirus infection on the nk cell receptor repertoire
Blood, 2004Co-Authors: Monica Guma, Ana Angulo, Carlos Vilches, Natalia Gomezlozano, Nuria Malats, Miguel LopezbotetAbstract:Expression of the activating CD94/NKG2C killer lectin-like receptor (KLR) specific for HLA-E was analyzed in peripheral blood lymphocytes (PBLs) from healthy adult blood donors; the expression of other natural killer (NK) cell receptors (ie, CD94/NKG2A, KIR, CD85j, CD161, NKp46, NKp30, and NKG2D) was also studied. Human cytomegalovirus (HCMV) infection as well as the HLA-E and killer immunoglobulin-like receptor (KIR) genotypes were considered as potentially relevant variables associated with CD94/NKG2C expression. The proportion of NKG2C+ lymphocytes varied within a wide range (
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imprint of human cytomegalovirus infection on the nk cell receptor repertoire
Blood, 2004Co-Authors: Monica Guma, Ana Angulo, Carlos Vilches, Natalia Gomezlozano, Nuria Malats, Miguel LopezbotetAbstract:Expression of the activating CD94/NKG2C killer lectin-like receptor (KLR) specific for HLA-E was analyzed in peripheral blood lymphocytes (PBLs) from healthy adult blood donors; the expression of other natural killer (NK) cell receptors (ie, CD94/NKG2A, KIR, CD85j, CD161, NKp46, NKp30, and NKG2D) was also studied. Human cytomegalovirus (HCMV) infection as well as the HLA-E and killer immunoglobulin-like receptor (KIR) genotypes were considered as potentially relevant variables associated with CD94/NKG2C expression. The proportion of NKG2C+ lymphocytes varied within a wide range (<0.1% to 22.1%), and a significant correlation ( r = 0.83; P < .001) between NKG2C+ NK and T cells was noticed. The HLA-E genotype and the number of activating KIR genes of the donors were not significantly related to the percentage of NKG2C+ lymphocytes. By contrast, a positive serology for HCMV, but not for other herpesviruses (ie, Epstein-Barr and herpes simplex), turned out to be strongly associated ( P < .001) with increased proportions of NKG2C+ NK and T cells. Remarkably, the CD94/NKG2C+ population expressed lower levels of natural cytotoxicity receptors (NCRs) (ie, NKp30, NKp46) and included higher proportions of KIR+ and CD85j+ cells than CD94/NKG2A+ cells. Altogether, these data support that HCMV infection selectively shapes the natural killer cell receptor (NKR) repertoire of NK and T cells from healthy carrier individuals.
Alessandro Moretta - One of the best experts on this subject based on the ideXlab platform.
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analysis of memory like natural killer cells in human cytomegalovirus infected children undergoing αβ t and b cell depleted hematopoietic stem cell transplantation for hematological malignancies
Haematologica, 2016Co-Authors: Letizia Muccio, Miguel Lopezbotet, Michela Falco, Alice Bertaina, Franco Locatelli, Lorenzo Moretta, Alessandro Moretta, Daniela Pende, Raffaella Meazza, Mariella Della ChiesaAbstract:We analyzed the impact of human cytomegalovirus infection on the development of natural killer cells in 27 pediatric patients affected by hematological malignancies, who had received a HLA-haploidentical hematopoietic stem cell transplantation, depleted of both α/β+ T cells and B cells. In line with previous studies in adult recipients of umbilical cord blood transplantation, we found that human cytomegalovirus reactivation accelerated the emergence of mature natural killer cells. Thus, most children displayed a progressive expansion of a memory-like natural killer cell subset expressing NKG2C, a putative receptor for human cytomegalovirus, and CD57, a marker of terminal natural killer cell differentiation. NKG2C+CD57+ natural killer cells were detectable by month 3 following hematopoietic stem cell transplantation and expanded until at least month 12. These cells were characterized by high killer Ig-like receptors (KIRs) and leukocyte inhibitory receptor 1 (LIR-1) and low Siglec-7, NKG2A and Interleukin-18Rα expression, killed tumor targets and responded to cells expressing HLA-E (a NKG2C ligand). In addition, they were poor Interferon-γ producers in response to Interleukin-12 and Interleukin-18. The impaired response to these cytokines, together with their highly differentiated profile, may reflect their skewing toward an adaptive condition specialized in controlling human cytomegalovirus. In conclusion, in pediatric patients receiving a type of allograft different from umbilical cord blood transplantation, human cytomegalovirus also induced memory-like natural killer cells, possibly contributing to controlling infections and reinforcing anti-leukemia effects.
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human cytomegalovirus infection promotes rapid maturation of nk cells expressing activating killer ig like receptor in patients transplanted with NKG2c umbilical cord blood
Journal of Immunology, 2014Co-Authors: Mariella Della Chiesa, Michela Falco, Alice Bertaina, Letizia Muccio, Claudia Alicata, Francesco Frassoni, Franco Locatelli, Lorenzo Moretta, Alessandro MorettaAbstract:NK cells are the first lymphoid population recovering after allogeneic hematopoietic stem cell transplantation and play a crucial role in early immunity after the graft. Recently, it has been shown that human CMV (HCMV) infection/reactivation can deeply influence NK cell reconstitution after umbilical cord blood transplantation by accelerating the differentiation of mature NKG2A−killer Ig-like receptor (KIR)+ NK cells characterized by the expression of the NKG2C-activating receptor. In view of the hypothesis that NKG2C could be directly involved in NK cell maturation driven by HCMV infection, we analyzed the maturation and function of NK cells developing in three patients with hematological malignancies given umbilical cord blood transplantation from donors carrying a homozygous deletion of the NKG2C gene. We show that HCMV infection can drive rapid NK maturation, characterized by the expansion of CD56dimNKG2A−KIR+ cells, even in the absence of NKG2C expression. Interestingly, this expanded mature NK cell subset expressed surface-activating KIR that could trigger NK cell cytotoxicity, degranulation, and IFN-γ release. Given the absence of NKG2C, it is conceivable that activating KIRs may play a role in the HCMV-driven NK cell maturation and that NK cells expressing activating KIRs might contribute, at least in part, to the control of infections after transplantation.
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phenotypic and functional heterogeneity of human nk cells developing after umbilical cord blood transplantation a role for human cytomegalovirus
Blood, 2012Co-Authors: Mariella Della Chiesa, Michela Falco, Francesco Frassoni, Franco Locatelli, Lorenzo Moretta, Marina Podesta, Alessandro MorettaAbstract:Natural killer (NK) cells play a crucial role in early immunity after hematopoietic stem cell transplantation because they are the first lymphocyte subset recovering after the allograft. In this study, we analyzed the development of NK cells after intrabone umbilical cord blood (CB) transplantation in 18 adult patients with hematologic malignancies. Our data indicate that, also in this transplantation setting, NK cells are the first lymphoid population detectable in peripheral blood. However, different patterns of NK-cell development could be identified. Indeed, in a group of patients, a relevant fraction of NK cells expressed a mature phenotype characterized by the KIR+NKG2A− signature 3-6 months after transplantation. In other patients, most NK cells maintained an immature phenotype even after 12 months. A possible role for cytomegalovirus in the promotion of NK-cell development was suggested by the observation that a more rapid NK-cell maturation together with expansion of NKG2C+ NK cells was confined to patients experiencing cytomegalovirus reactivation. In a fraction of these patients, an aberrant and hyporesponsive CD56−CD16+p75/AIRM1− NK-cell subset (mostly KIR+NKG2A−) reminiscent of that described in patients with viremic HIV was detected. Our data support the concept that cytomegalovirus infection may drive NK-cell development after umbilical CB transplantation.
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NKp46 and DNAM-1 NK-cell receptors drive the response to human cytomegalovirus-infected myeloid dendritic cells overcoming viral immune evasion strategies
Blood, 2010Co-Authors: Giuliana Magri, Ana Angulo, Hartmut Hengel, Alessandro Moretta, Aura Muntasell, Neus Romo, Andrea Sáez-borderías, Daniela Pende, Daniel E. Geraghty, Miguel López-botetAbstract:Information on natural killer (NK)-cell receptor-ligand interactions involved in the response to human cytomegalovirus (HCMV) is limited and essentially based on the study of infected fibroblasts. Experimental conditions were set up to characterize the NK response to HCMV-infected myeloid dendritic cells (DCs). Monocyte-derived DCs (moDCs) infected by the TB40/E HCMV strain down-regulated the expression of human leukocyte antigen class I molecules and specifically activated autologous NK-cell populations. NKG2D ligands appeared virtually undetectable in infected moDCs, reflecting the efficiency of immune evasion mechanisms, and explained the lack of antagonistic effects of NKG2D-specific monoclonal antibody. By contrast, DNAM-1 and DNAM-1 ligands (DNAM-1L)-specific monoclonal antibodies inhibited the NK response at 48 hours after infection, although the impact of HCMV-dependent down-regulation of DNAM-1L in infected moDCs was perceived at later stages. moDCs constitutively expressed ligands for NKp46 and NKp30 natural cytotoxicity receptors, which were partially reduced on HCMV infection; yet, only NKp46 appeared involved in the NK response. In contrast to previous reports in fibroblasts, human leukocyte antigen-E expression was not preserved in HCMV-infected moDCs, which triggered CD94/NKG2A(+) NK-cell activation. The results provide an insight on key receptor-ligand interactions involved in the NK-cell response against HCMV-infected moDCs, stressing the importance of the dynamics of viral immune evasion mechanisms.
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the cd94 and NKG2 a c type lectins covalently assemble to form a natural killer cell inhibitory receptor for hla class i molecules
European Journal of Immunology, 1997Co-Authors: Marta Carretero, Lorenzo Moretta, Alessandro Moretta, Juan J Perezvillar, Teresa Bellon, Claudia Cantoni, Cristina Bottino, Roberto Biassoni, Antonio RodriguezAbstract:CD94, a type II membrane protein containing a C-type lectin domain, has been shown to be involved in natural killer (NK) cell-mediated recognition of different HLA allotypes. The inhibitory form of the CD94 receptor has recently been identified by the specific monoclonal antibody (mAb) Z199. Herein, we demonstrate that the inhibitory receptor is in fact a complex formed by the covalent association of CD94 with the NKG2-A molecule (Mr approximately 43 kDa), another member of the C-type lectin superfamily, and that Z199 mAb specifically recognize NKG2-A molecules. Although the NKG2-A-encoding cDNA has been known for several years, the corresponding protein and its possible function remained undefined. Moreover, we show that the NKG2-B protein, an alternatively spliced product of the NKG2-A gene, can also assemble with CD94. Remarkably, both NKG2-A and NKG2-B proteins contain cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIM). This may provide the molecular basis of the inhibitory function mediated by the CD94/NKG2-A receptor complexes.
John E. Coligan - One of the best experts on this subject based on the ideXlab platform.
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cd94 NKG2a inhibits nk cell activation by disrupting the actin network at the immunological synapse
Journal of Immunology, 2006Co-Authors: Madhan Masilamani, Juraj Kabat, Francisco Borrego, Connie Nguyen, John E. ColiganAbstract:An adequate immune response is the result of the fine balance between activation and inhibitory signals. The exact means by which inhibitory signals obviate activation signals in immune cells are not totally elucidated. Human CD94/NKG2A is an ITIM-containing inhibitory receptor expressed by NK cells and some CD8+ T cells that recognize HLA-E. We show that the engagement of this receptor prevents NK cell activation by disruption of the actin network and exclusion of lipid rafts at the point of contact with its ligand (inhibitory NK cell immunological synapse, iNKIS). CD94/NKG2A engagement leads to recruitment and activation of src homology 2 domain-bearing tyrosine phosphatase 1. This likely explains the observed dephosphorylation of guanine nucleotide exchange factor and regulator of actin, Vav1, as well as ezrin-radixin-moesin proteins that connect actin filaments to membrane structures. In contrast, NK cell activation by NKG2D induced Vav1 and ezrin-radixin-moesin phosphorylation. Thus, CD94/NKG2A prevents actin-dependent recruitment of raft-associated activation receptors complexes to the activating synapse. This was further substantiated by showing that inhibition of actin polymerization abolished lipid rafts exclusion at the iNKIS, whereas cholesterol depletion had no effect on actin disruption at the iNKIS. These data indicate that the lipid rafts exclusion at the iNKIS is an active process which requires an intact cytoskeleton to maintain lipid rafts outside the inhibitory synapse. The net effect is to maintain an inhibitory state in the proximity of the iNKIS, while allowing the formation of activation synapse at distal points within the same NK cell.
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nk cell cd94 NKG2a inhibitory receptors are internalized and recycle independently of inhibitory signaling processes
Journal of Immunology, 2002Co-Authors: Francisco Borrego, Juraj Kabat, Tolib B Sanni, John E. ColiganAbstract:Human CD94/NKG2A is an inhibitory receptor that recognizes HLA-E and is expressed by NK cells and a subset of T cells. We have analyzed the cellular trafficking of the CD94/NKG2A receptor using the NKL cell line and peripheral blood NK cells. Flow cytometric, confocal microscopic, and biochemical analyses show that CD94/NKG2A continuously recycles in an active process that requires the cytoskeleton between the cell surface and intracellular compartments that are distinguishable from recycling compartments used by well-characterized receptors, such as transferrin receptor (CD71). CD94/NKG2A, an inhibitory receptor, traffics differently from the closely related CD94/NKG2C molecule, an activating receptor. Using transfection/expression analyses of wild-type and mutant CD94/NKG2A molecules in the HLA-E negative rat basophilic cell line RBL-2H3, we demonstrate that CD94/NKG2A internalization is independent of ligand cross-linking or the presence of functional immunoreceptor tyrosine-based inhibition motifs. Thus, the mechanisms that control cell surface homeostasis of CD94/NKG2A are independent of functional signaling.
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structure and function of major histocompatibility complex mhc class i specific receptors expressed on human natural killer nk cells
Molecular Immunology, 2002Co-Authors: Francisco Borrego, Juraj Kabat, Louis D Lieto, Kerima Maasho, Jose Pena, Rafael Solana, John E. ColiganAbstract:Abstract Natural killer (NK) cells express receptors that are specific for MHC class I molecules. These receptors play a crucial role in regulating the lytic and cytokine expression capabilities of NK cells. In humans, three distinct families of genes have been defined that encode for receptors of HLA class I molecules. The first family identified consists of type I transmembrane molecules belonging to the immunoglobulin (Ig) superfamily and are called killer cell Ig-like receptors (KIR). A second group of receptors belonging to the Ig superfamily, named ILT (for immunoglobulin like transcripts), has more recently been described. ILTs are expressed mainly on B, T and myeloid cells, but some members of this group are also expressed on NK cells. They are also referred to as LIRs (for leukocyte Ig-like receptor) and MIRs (for macrophage Ig-like receptor). The ligands for the KIR and some of the ILT receptors include classical (class Ia) HLA class I molecules, as well as the nonclassical (class Ib) HLA-G molecule. The third family of HLA class I receptors are C-type lectin family members and are composed of heterodimers of CD94 covalently associated with a member of the NKG2 family of molecules. The ligand for most members is the nonclassical class I molecule HLA-E. NKG2D, a member of the NKG2 family, is expressed as a homodimer, along with the adaptor molecule DAP10. The ligands of NKG2D include the human class I like molecules MICA and MICB, and the recently described ULBPs. Each of these three families of receptors has individual members that can recognize identical or similar ligands yet signal for activation or inhibition of cellular functions. This dichotomy correlates with particular structural features present in the transmembrane and intracytoplasmic portions of these molecules. In this review we will discuss the molecular structure, specificity, cellular expression patterns, and function of these HLA class I receptors, as well as the chromosomal location and genetic organization.
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hla e is the ligand for the natural killer cell cd94 NKG2 receptors
Journal of Biomedical Science, 1998Co-Authors: Phillip Posch, Francisco Borrego, Andrew G Brooks, John E. ColiganAbstract:CD94/NKG2 is a recently described receptor present on natural killer (NK) cells and certain T cells that is composed of the CD94 chain covalently associated with a member of the NKG2 family of molecules. Both chains are glycosylated members of the C-type lectin superfamily. The CD94/NKG2 receptors are functionally heterogenous depending on which NKG2 family member is associated with CD94. Initially, it was thought that CD94/NKG2 receptors recognized a broad array of HLA-A, -B and -C (classical), as well as the nonclassical HLA-G, MHC class I molecules. Instead, recent data have suggested that this receptor is specific for HLA-E complexed with a peptide derived from the signal sequence (residues 3–11) of certain classical MHC class I molecules. Position 2 (residue 4) in the signal sequence derived peptides appears pivotal in determining whether the HLA-E/peptide complex confers resistance to NK-mediated lysis. The potential roles that the CD94/NKG2-HLA-E receptor ligand interaction might play in infection and tumor development are discussed.
Lewis L Lanier - One of the best experts on this subject based on the ideXlab platform.
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cutting edge NKG2chicd57 nk cells respond specifically to acute infection with cytomegalovirus and not epstein barr virus
Journal of Immunology, 2014Co-Authors: Deborah W Hendricks, Henry H Balfour, Samantha K Dunmire, David O Schmeling, Kristin A Hogquist, Lewis L LanierAbstract:CMV induces the expansion of a unique subset of human NK cells expressing high levels of the activating CD94-NKG2C receptor that persist after control of the infection. We investigated whether this subset is CMV specific or is also responsive to acute infection with EBV. We describe a longitudinal study of CMV(-) and CMV(+) students who were acutely infected with EBV. The NKG2C(hi) NK subset was not expanded by EBV infection. However, EBV infection caused a decrease in the absolute number of immature CD56(bright)CD16(-) NK cells in the blood and, in CMV(+) individuals, induced an increased frequency of mature CD56(dim)NKG2A(+)CD57(+) NK cells in the blood that persisted into latency. These results provide further evidence that NKG2C(+) NK cells are CMV specific and suggest that EBV infection alters the repertoire of NK cells in the blood.
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skewed distribution of natural killer cells in psoriasis skin lesions
Experimental Dermatology, 2013Co-Authors: Lewis L Lanier, Jeffrey M Milush, Vanessa A York, Mariana Dias Batista, Peter J Kuebler, Esper G Kallas, David S Chang, Wilson Liao, Patrick UnemoriAbstract:Psoriasis is a hyper-proliferative disease of the skin in which immunological mechanisms play a direct pathogenetic role. There have been limited studies of natural killer (NK) cells in psoriasis. The aim of this study was to examine the phenotype of NK cells in skin biopsies and peripheral blood mononuclear cells from patients with psoriasis and healthy controls. CD56(+) CD16(-) and CD56(+) CD16(+) NK cells were isolated from lesional skin, unaffected skin and PBMC of psoriasis patients, and normal skin and PBMC from healthy controls. The expression of CD57, NKG2A and NKG2C was assessed by flow cytometry. NK cells in psoriasis skin lesions were skewed in their expression of CD57, a marker of NK cell maturity, with CD57 expression significantly reduced and NKG2A expression increased on NK cells in lesional and unaffected skin compared to controls. These data suggest that in this patient cohort, NK cells could be isolated from psoriasis lesions and exhibit an immature phenotype.
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cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2c natural killer cells with potent function
Blood, 2012Co-Authors: Bree Foley, Lewis L Lanier, Sarah Cooley, Sandra Lopezverges, Michael R Verneris, Michelle Pitt, Julie M Curtsinger, Daniel J Weisdorf, Jeffrey S. MillerAbstract:During mouse cytomegalovirus (CMV) infection, a population of Ly49H+ natural killer (NK) cells expands and is responsible for disease clearance through the induction of a “memory NK-cell response.” Whether similar events occur in human CMV infection is unknown. In the present study, we characterized the kinetics of the NK-cell response to CMV reactivation in human recipients after hematopoietic cell transplantation. During acute infection, NKG2C+ NK cells expanded and were potent producers of IFNγ. NKG2C+ NK cells predominately expressed killer cell immunoglobulin–like receptor, and self-killer cell immunoglobulin–like receptors were required for robust IFNγ production. During the first year after transplantation, CMV reactivation induced a more mature phenotype characterized by an increase in CD56dim NK cells. Strikingly, increased frequencies of NKG2C+ NK cells persisted and continued to increase in recipients who reactivated CMV, whereas these cells remained at low frequency in recipients without CMV reactivation. Persisting NKG2C+ NK cells lacked NKG2A, expressed CD158b, preferentially acquired CD57, and were potent producers of IFNγ during the first year after transplantation. Recipients who reactivated CMV also expressed higher amounts of IFNγ, T-bet, and IL-15Rα mRNA transcripts. Our findings support the emerging concept that CMV-induced innate memory-cell populations may contribute to malignant disease relapse protection and infectious disease control long after transplantation.
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a signal peptide derived from hsp60 binds hla e and interferes with cd94 NKG2a recognition
Journal of Experimental Medicine, 2002Co-Authors: Jakob Michaelsson, Cristina Teixeira De Matos, Adnane Achour, Lewis L Lanier, Klas Karre, Kalle SoderstromAbstract:Human histocompatibility leukocyte antigen (HLA)-E is a nonclassical major histocompatibility complex (MHC) class I molecule which presents a restricted set of nonameric peptides, derived mainly from the signal sequence of other MHC class I molecules. It interacts with CD94/NKG2 receptors expressed on the surface of natural killer (NK) cells and T cell subsets. Here we demonstrate that HLA-E also presents a peptide derived from the leader sequence of human heat shock protein 60 (hsp60). This peptide gains access to HLA-E intracellularly, resulting in up-regulated HLA-E/hsp60 signal peptide cell-surface levels on stressed cells. Notably, HLA-E molecules in complex with the hsp60 signal peptide are no longer recognized by CD94/NKG2A inhibitory receptors. Thus, during cellular stress an increased proportion of HLA-E molecules may bind the nonprotective hsp60 signal peptide, leading to a reduced capacity to inhibit a major NK cell population. Such stress induced peptide interference would gradually uncouple CD94/NKG2A inhibitory recognition and provide a mechanism for NK cells to detect stressed cells in a peptide-dependent manner.
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functionally and structurally distinct nk cell receptor repertoires in the peripheral blood of two human donors
Immunity, 1997Co-Authors: Nicholas M Valiante, Joseph H Phillips, Annalisa Dandrea, Markus Uhrberg, Heather G Shilling, K Lienertweidenbach, Kelly L Arnett, Lewis L LanierAbstract:Abstract The expression of KIR and CD94:NKG2 receptors was determined for more than 100 natural killer (NK) cell clones obtained from two blood donors who differ in their HLA class I and KIR genes. More than 98% of the clones were inhibited by individual autologous class I allotypes, and every clone was inhibited by the combination of autologous allotypes. The patterns of inhibition correlate with expression of inhibitory receptors of defined specificity. One donor possesses three class I ligands for KIR, and a majority of NK cells use KIR as their inhibitory receptor; the second donor possesses only a single ligand for KIR, and a majority of NK cells use the more broadly reactive CD94:NKG2a as their inhibitory receptor. Because of these differences, the first donor has subpopulations of NK cells that kill cells of the second donor, whereas the NK cells of the second donor are universally tolerant of cells from the first donor.
Francisco Navarro - One of the best experts on this subject based on the ideXlab platform.
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mitogen activated protein kinase activity is involved in effector functions triggered by the cd94 NKG2 c nk receptor specific for hla e
European Journal of Immunology, 2000Co-Authors: Marta Carretero, Francisco Navarro, Manuel Llano, Teresa Bellon, Miguel LopezbotetAbstract:The CD94/NKG2C heterodimer constitutes an activating receptor involved in NK cell-mediated recognition of the class lb molecule HLA-E. It transduces the triggering signal through an ITAM-bearing molecule, DAP12/KARAP, coupled non-covalently to the receptor. Here we show that specific engagement of the receptor complex expressed on the surface of an NK clone induced the phosphorylation of mitogen-activated protein kinase (MAPK). By the use of the MEK inhibitor PD098059 we demonstrate that the MAPK pathway participates in the CD94-dependent TNF-alpha production and cytotoxicity. Moreover, we transferred the activating function by transfection of the heterologous RBL cell line with CD94/NKG2-C/DAP12. In this system, cross-linking of the receptor induced calcium mobilization, serotonin release and phosphorylation of MAPK.
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hla e bound peptides influence recognition by inhibitory and triggering cd94 NKG2 receptors preferential response to an hla g derived nonamer
European Journal of Immunology, 1998Co-Authors: Manuel Llano, Daniel E. Geraghty, Ni Lee, Francisco Navarro, Pilar Garcia, Juan Pablo Albar, Miguel LopezbotetAbstract:The HLA-E class Ib molecule constitutes a major ligand for the lectin-like CD94/NKG2 natural killer (NK) cell receptors. Specific HLA class I leader sequence-derived nonapeptides bind to endogenous HLA-E molecules in the HLA-defective cell line 721.221, inducing HLA-E surface expression, and promote CD94/NKG2A-mediated recognition. We compared the ability of NK clones which expressed either inhibitory or activating CD94/NKG2 receptors to recognize HLA-E molecules on the surface of 721.221 cells loaded with a panel of synthetic nonamers derived from the leader sequences of most HLA class I molecules. Our results support the notion that the primary structure of the HLA-E-bound peptides influences CD94/ NKG2-mediated recognition, beyond their ability to stabilize surface HLA-E. Further, CD94/ NKG2A+ NK clones appeared more sensitive to the interaction with most HLA-E-peptide complexes than did effector cells expressing the activating CD94/NKG2C receptor. However, a significant exception to this pattern was HLA-E loaded with the HLA-G-derived nonamer. This complex triggered cytotoxicity very efficiently over a wide range of peptide concentrations, suggesting that the HLA-E/G-nonamer complex interacts with the CD94/NKG2 triggering receptor with a significantly higher affinity. These results raise the possibility that CD94/NKG2-mediated recognition of HLA-E expressed on extravillous cytotrophoblasts plays an important role in maternal-fetal cellular interactions.
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the cd94 NKG2 c type lectin receptor complex
Current Topics in Microbiology and Immunology, 1998Co-Authors: Miguel Lopezbotet, Juan J Perezvillar, Manuel Llano, Francisco Navarro, Marta Carretero, Teresa BellonAbstract:A multigene family of human Ig-SF receptors and members of the murine Ly49 C-type lectin family are involved in natural killer (NK) cell-mediated recognition of MHC class I molecules. The human CD94 glycoprotein covalently assembles with different C-type lectins of the NKG2 family. By functional criteria, the CD94/ NKG2-A (kp43) receptor complex appears also involved in NK cell-mediated recognition of different HLA class I allotypes. Similarly to the other NK inhibitory receptors, NKG2-A contains cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs). By contrast, NK clones bearing a different receptor complex (CD94/ p39) are triggered upon ligation by CD94-specific monoclonal antibodies (MAbs); the p39 subunit is likely encoded by other member(s) of the NKG2 family. Expression of the different CD94/ NKG2 complexes is warranted to precisely assess their specific interaction with HLA class I molecules, and the molecular basis for their divergent functional properties.
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the cd94 NKG2 c type lectin receptor complex involvement in nk cell mediated recognition of hla class i molecules
Immunologic Research, 1997Co-Authors: Miguel Lopezbotet, Juan J Perezvillar, Manuel Llano, Marta Carretero, Teresa Bellon, Francisco NavarroAbstract:A multigene family to human Ig-SF receptors and members of the murine Ly49 C-type lectin family are involved in natural killer (NK) cell-mediated recognition of MHC class I molecules. The human CD94 glycoprotein covalently assembles with different C-type lectins of the NKG2 family. By functional criteria, the CD94/NKG2-A (kp43) receptor complex appears also involved in NK cell-mediated recognition of different HLA class I allotypes. Similarly to the other NK inhibitory receptors, NKG2-A contains cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMS). By contrast, NK clones bearing different receptor complex (CD94/p39) are triggered upon ligation by CD94-specific monoclonal antibodies (MAbs); the p39 subunit is likely encoded by other member(s) of the NKG2 family. Expression of different CD94/NKG2 complexes is warranted to precisely assess their specific interaction with HLA class I molecules, and the molecular basis for their divergent functional properties.