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PubMed2026

Clonal stochasticity in early NK cell response to mouse cytomegalovirus is generated by mature subsets of varying proliferative ability.

Natural killer (NK) cells are classically defined as innate immune cells, but experiments show that mouse cytomegalovirus (MCMV) infection in C57BL/6 mice can cause NK cells to undergo antigen-specific proliferation and memory formation, similar to adaptive CD8+ T cells. One shared behavior between CD8+ T cells and NK cells is clonal expansion, where a single stimulated cell proliferates rapidly to form a diverse population of cells. For example, clones derived from single cells are most abundant during expansion when they are primarily CD27- for NK cells and CD62L- for T cells, phenotypes derived from precursor CD27+ and CD62L + cells, respectively. Here we determined the mechanistic rules involving proliferation, cell death, and differentiation of endogenous and adoptively transferred NK cells in the expansion phase of the response to MCMV infection. We found that the interplay between cell proliferation and cell death of mature CD27- NK cells and a highly proliferative CD27-Ly6C- mature subtype and intrinsic stochastic fluctuations in these processes play key roles in regulating the heterogeneity and population of the NK cell subtypes. Furthermore, we estimate rates for maturation of endogenous NK cells in homeostasis and in MCMV infection and found that only NK cell growth rates, and not differentiation rates, are appreciably increased by MCMV. Taken together, these results quantify the differences between the kinetics of NK cell antigen-specific expansion from that of CD8+T cells and unique mechanisms that give rise to the observed heterogeneity in NK cell clones generated from single NK cells in the expansion phase.

Animals↗

PubMed1999

Characterization of Epstein-Barr virus (EBV)-infected natural killer (NK) cell proliferation in patients with severe mosquito allergy; establishment of an IL-2-dependent NK-like cell line.

The clinical evidence of a relationship between severe hypersensitivity to mosquito bite (HMB) and clonal expansion of EBV-infected NK cells has been accumulated. In order to clarify the mechanism of EBV-induced NK cell proliferation and its relationship with high incidence of leukaemias or lymphomas in HMB patients, we studied clonally expanded NK cells from three HMB patients and succeeded in establishing an EBV-infected NK-like cell line designated KAI3. Immunoblotting and reverse transcriptase-polymerase chain reaction (RT-PCR) analyses revealed that KAI3 cells as well as infected NK cells exhibited an EBV latent infection type II, where EBV gene expression was limited to EBNA 1 and LMP1. As KAI3 was established by culture with IL-2, IL-2 responsiveness of peripheral blood NK cells from patients was examined. The results represented markedly augmented IL-2-induced IL-2R alpha expression in NK cells. This characteristic property may contribute to the persistent expansion of infected NK cells. However, KAI3 cells as well as the NK cells from patients were not protected from apoptosis induced by either an anti-Fas antibody or NK-sensitive K562 cells. Preserved sensitivity to apoptosis might explain the relatively regulated NK cell numbers in the peripheral blood of the patients. To our knowledge, KAI3 is the first reported NK-like cell line established from patients of severe chronic active EBV infection (SCAEBV) before the onset of leukaemias or lymphomas. KAI3 cells will contribute to the study of EBV persistency in the NK cell environment and its relationship with high incidence of leukaemias or lymphomas in HMB patients.

Adolescent↗

PubMed1987

Functional analysis of a clonal expansion of Leu 11 positive NK active lymphoid cells.

A female patient with an unusual lymphoproliferative disease associated with marked neutropenia has been observed for 36 months. The expanded cell population consists of large lymphocytes, many of which contain large azurophilic granules with acid phosphatase activity. These cells were T3, T8, T11 and Leu 11 positive but lacked the M1, T10, IL-2 receptor and HLA.DR antigens. The majority of these cells (60-70%) were also Leu 7 (HNK-1) positive. Strong natural killer (NK) activity was found in both the Leu 7 positive and negative cell populations. This cytotoxic activity was inhibited by monoclonal antibodies known to inhibit NK activity but was unaffected by antibodies which block T cell and T/NK cell cytotoxicity. Further functional analysis indicated that these cells suppressed normal T cell responses to mitogens, MLC responses and PWM induced B cell immunoglobulin synthesis. No effect on bone marrow progenitor cell growth was demonstrated. Antibody dependent cellular cytotoxic (ADCC) activity was barely detectable despite the presence of the Leu 11 antigen. Southern blot DNA analysis demonstrated clonal rearrangement of the T cell receptor beta gene thereby confirming that this variant of T gamma lymphoproliferative disease was a neoplastic condition.

Adult↗

PubMed1996

Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation.

Mice homozygous for an Ikaros null mutation display distinct defects in the development of fetal and adult lymphocytes. Fetal T lymphocytes, and fetal and adult B lymphocytes and their earliest progenitors are absent. Postnatally, hematopoietic stem cells give rise to thymocyte precursors that undergo aberrant differentiation into the CD4 lineage and clonal expansion. The lack of NK cells and some gamma delta T cell subsets and a large reduction in thymic dendritic APCs suggest that Ikaros is essential for establishing early branch points in the postnatal T cell pathway. The lymphoid defects detected in Ikaros null mice reveal critical molecular differences between fetal and postnatal hematopoietic progenitors that dictate their ability to give rise to T cells. These studies also establish Ikaros as a tumor suppressor gene acting during thymocyte differentiation. Phenotypic comparison of this null mutation with a severe dominant-negative Ikaros mutation identifies molecular redundancy in the postnatal hemolymphoid system.

Animals↗

PubMed2001

Role of the complementarity-determining region 3 (CDR3) of the TCR-beta chains associated with the V alpha 14 semi-invariant TCR alpha-chain in the selection of CD4+ NK T Cells.

The NK1.1(+)TCRalphabeta(int) CD4(+), or double negative T cells (NK T cells) consist of a mixture of CD1d-restricted and CD1d-unrestricted cells. The relationships between CD4(+)NK1.1(+) T cells and conventional T cells are not understood. To compare their respective TCR repertoires, NK1.1(+)TCRalphabeta(int), CD4(+) T cells have been sorted out of the thymus, liver, spleen, and bone marrow of C57BL/6 mice. Molecular analysis showed that thymus and liver used predominantly the Valpha14-Jalpha281 and Vbeta 2, 7, and 8 segments. These cells are CD1d restricted and obey the original definition of NK T cells. The complementarity-determining region 3 (CDR3) sequences of the TCR Vbeta8.2-Jbeta2.5 chain of liver and thymus CD4(+) NK T cells were determined and compared with those of the same rearrangements of conventional CD4(+) T cells. No amino acid sequence or usage characteristic of NK T cells could be evidenced: the Vbeta8.2-Jbeta2.5 diversity regions being primarily the same in NK T and in T cells. No clonal expansion of the beta-chains was observed in thymus and liver CD1d-restricted CD4(+)NK T cells, suggesting the absence of acute or chronic Ag-driven stimulation. Molecular analysis of the TCR used by Valpha14-Jalpha281 transgenic mice on a Calpha(-/-) background showed that the alpha-chain can associate with beta-chains using any Vbeta segment, except in NK T cells in which it paired predominately with Vbeta 2, 7, and 8(+) beta-chains. The structure of the TCR of NK T cells thus reflects the affinity for the CD1d molecule rather than a structural constraint leading to the association of the invariant alpha-chain with a distinctive subset of Vbeta segment.

Animals↗

PubMed2001

Impaired cytotoxic T lymphocyte response to Epstein-Barr virus-infected NK cells in patients with severe chronic active EBV infection.

Clinical evidence of a relationship between severe chronic active Epstein-Barr virus (EBV) infection and clonal expansion of EBV-infected T or NK cells has been accumulated. In order to clarify pathogenesis of EBV-infected cell proliferation in patients with severe chronic active EBV infection, cytotoxic T lymphocyte (CTL) responses of two patients against B-lymphoblastoid cell lines (B-LCL) and EBV-infected NK cells were examined in comparison with those of HLA-identical healthy siblings. Unexpectedly, patients' CTL activities induced by mixed culture with autologous B-LCLs were markedly reduced, although uncontrolled EBV-related B-cell proliferations have never been experienced. In contrast, limiting dilution analysis demonstrated that B-LCL-specific CTL precursor (CTLp) frequencies of patients were comparable to those of their healthy sisters. The existence of normal levels of B-LCL-specific T cell responses was confirmed by flow-cytometric analysis of IFN-gamma-producing T cells after stimulation with B-LCLs. Infected NK-cell-specific CTLp frequencies of the patients were at undetectable levels despite their expression of latent membrane protein (LMP) 1, suggesting mechanisms to escape immunologic surveillance. In the patients' HLA-identical healthy sisters, infected NK-cell-specific CTLps were detected, and infected NK-cell-specific CTL clones could be established. From these findings, two treatment options for severe chronic active EBV infection are offered for consideration: adoptive transfer of in vitro-cultured CTL, and bone marrow transplantation from HLA-identical donors.

Adolescent↗

PubMed1985

Generation of natural killer cell lines from murine long-term bone marrow cultures.

Functionally active natural killer (NK) cells with the ability to lyse 51Cr-labeled YAC-1 lymphoma target cells are no longer detectable by 1 wk of culture in cultured marrow cells harvested from Dexter-type long-term marrow cultures (LMC). Interferon, which enhances NK cell-mediated target cell lysis, fails to induce NK activity from LMC cells even at high effector to target cell ratios. However, such LMC cells, when placed in secondary cultures in the presence of Con A-splenic leukocyte-conditioned medium (spleen-CM) generated a population of cells with NK activity within 1 wk. Kinetic studies showed that the generation of NK activity was not due simply to proliferation of a few surviving NK cells, but suggested derivation from NK precursors through clonal expansion and functional maturation. This NK activity was further shown to be associated with a subpopulation of cells bearing surface Thy-1, Ly-5, and NK-1 as well as asialo-GM1 antigens but lacking Ly-1 antigen. The expression of Ly-2 antigen, however, was variable. Electron microscopy studies of isolated asialo-GM1-positive cells showed a uniform lymphoblastoid morphology with large cytoplasmic to nuclear ratios and prominent electron dense cytoplasmic granules characteristic of large granular lymphocytes. In support of the NK nature of such cultured cells was the ability of anti-asialo-GM1 and complement to abrogate, and of interferon to augment, target cell lysis. Isolated cell lines also showed target selectivity similar to NK cells. The implications of the studies on further analysis of the nature of NK precursors is discussed.

Animals↗

PubMed2001

T-large granular lymphocyte leukemia accompanied by an increase of natural killer cells (CD3-) and associated with ulcerative colitis and autoimmune hepatitis.

Clonal expansion of large granular lymphocyte(LGL) have been classified into T-LGL and NK-LGL leukemia. T-LGL leukemia cells have a CD3+ phenotype and show clonal T-cell receptor(TCR) gene rearrangement. NK-LGL leukemia cells have a CD3- phenotype and no TCR gene rearrangement. We report a case of T-LGL leukemia accompanied by NK LGL expansions in a 65-year-old man who was observed 3 years earlier to have a LGL lymphocytosis in association with ulcerative colitis(UC) and autoimmune hepatitis (AIH). Phenotypic analysis of peripheral blood by flow cytometry disclosed an increase of both T-LGL(CD3+,CD56-,CD57+,and TCRalphabeta+) and NK-LGL (CD3-,CD16+,CD56+, and CD57+). Clonal rearrangement of the TCR beta gene was detected. A diagnosis of UC and AIH was made on the basis of the X-ray and mucosal biopsy findings of the large intestine, and on the scoring system for diagnosis of AIH, respectively. The disease was nonprogressive, and mesalazine and prednisolone were successful for treatment of UC and AIH. Previously reported cases of T-LGL, NK-LGL leukemia, or NK cell lymphocytosis had no association with UC or AIH, and there have been no reports having both T-LGL leukemia with T-cell receptor gene rearrangement and chronic NK cell lymphocytosis co-existing in a single patient.

Anti-Inflammatory Agents↗

PubMed1995

Contact-dependent endothelial class II HLA gene activation induced by NK cells is mediated by IFN-gamma-dependent and -independent mechanisms.

NK lymphocytes adhere avidly to allogeneic endothelial cells (ECs) and induce their membrane expression of MHC class II Ags in vitro. Endothelial class II expression augments EC-driven CD4+ T cell proliferation in vitro, and may amplify T cell recruitment and clonal expansion in vivo. Using an ex vivo lymphocyte-skin organ coculture model, NK cells could be found lining and inducing class II HLA on microvessel endothelium. Using neutralizing anti-IFN-gamma and anti-IFN-gamma receptor Abs, a spectrum of IFN-gamma dependence was observed for NK-mediated EC HLA-DR induction at the membrane and transcriptional levels, from negligible to moderate. Trans-well experiments displayed that direct NK-EC contact is required, and Ab inhibition studies indicated that the beta 2 integrin-ICAM-1 pathway(s) is critical in the generation of these responses. The use of HLA-DR alpha promoter constructs in transient transfection assays demonstrated that the highly conserved X and S transcription boxes are required in both IFN-gamma- and NK-mediated gene activation. As expected, because of the receptor species specificity, human IFN-gamma did not induce HLA-DR alpha promoter constructs transfected in Chinese hamster ovary cells, whereas NK cells did. Taken together, these results indicate that human allogeneic NK lymphocytes induce EC class II HLA gene activation and membrane expression in an adhesion-dependent, IFN-gamma-independent fashion and suggest that, in concert with any IFN-gamma-dependent component, this induction could represent an efficient mode of endothelial activation and immune amplification in vivo.

Antigens, Differentiation, B-Lymphocyte↗

PubMed2005

NK cells inhibit T cell proliferation via p21-mediated cell cycle arrest.

NK cells have been shown to influence immune responses via direct interaction with cells of the adaptive immune system, such as dendritic cells, B cells, and T cells. A role for NK cells in down-regulation of T cell responses has been implicated in several studies; however, the underlying mechanism of this suppression has remained elusive. In this study we show that dark Agouti rat NK cells inhibit syngeneic T cell proliferation via up-regulation of the cell cycle inhibitor, p21, resulting in a G0/G1 stage cell cycle arrest. The inhibition is cell-cell contact dependent, reversible, and Ag nonspecific. Interestingly, NK cells do not inhibit IL-2 secretion or IL-2R up-regulation and do not induce T cell death. Thus, our results show that NK cells do not affect early T cell activation events, but specifically inhibit T cell proliferation by direct interaction with T cells. Our findings suggest that NK cells may play an important role in maintaining immune homeostasis by directly regulating clonal expansion of activated T cells. This novel mechanism of T cell regulation by NK cells provides insight into NK cell-mediated regulation of adaptive immunity and provides a mechanistic link between NK cell function and suppression of T cell responses.

Animals↗

PubMed1992

Demonstration of clonality, by X-linked DNA analysis, in chronic natural killer cell lymphocytosis and successful therapy with oral cyclophosphamide.

The expanded lymphocyte population in large granular lymphocyte (LGL)-leukemia carries the phenotypic characteristics of either cytotoxic T lymphocytes (CD3+,CD8+) or natural killer (NK) cells (CD3-,CD15+). In the former subset, clonality has been demonstrated by T-cell receptor gene rearrangement studies. Since NK cells do not rearrange T-cell receptor genes, the neoplastic nature of chronic NK cell lymphocytosis has not been well defined. We used X-linked DNA analysis to study the clonal nature of an expanded NK cell population in a patient with a 3-year history of relative lymphocytosis associated with anemia and neutropenia. Southern blot analysis showed no clonal T-cell receptor gene rearrangement. The majority of the circulating lymphocytes had a NK cell phenotype and demonstrated both direct NK cell-mediated cytotoxicity and antibody-dependent cellular cytotoxicity. However, the in vitro growth characteristics of these cells did not suggest that they were polyclonal expansions of normal NK cells. To determine directly the clonal origin of these cells, we performed X-linked DNA analysis. Density gradient centrifugation methods were used to isolate mononuclear cells, and NK cells were positively selected by CD16-immunoconjugated magnetic beads. The DNA of these cells was analyzed by restriction fragment length polymorphism-methylation strategy and showed a monoclonal pattern of X-chromosome inactivation while a polyclonal pattern was obtained in corresponding skin tissue. Treatment of the patient with oral cyclophosphamide resulted in complete hematologic remission. We conclude that chronic NK lymphocytosis may be clonal and responsive to immunosuppressive therapy.

Aged↗

PubMed2000

Life, activation and death of intrahepatic lymphocytes in chronic hepatitis C.

The healthy liver of adult humans has little or no lymphocyte component and the histological finding of intrahepatic lymphocytes (IHL) is evidence of liver pathology. In a liver injured by chronic hepatitis C, the most common chronic liver disease, most IHL are activated/pro-inflammatory cells, which are particularly enriched for effectors of innate immunity (natural killer (NK), natural T, and other NK-like T cells). IHL do not undergo clonal expansion in the liver but migrate from extrahepatic sites to the chronically infected liver, where they display effector function and subsequently die, suggesting that maintenance of the IHL pool depends on continuous lymphocyte migration. The cytotoxic and inflammatory functions of these IHL have three potential outcomes: 1) they could be helpful in clearing the virus (a rare case in hepatitis C virus (HCV) infection); 2) they could be useless and have no effect on the infection; or 3) they could be harmful, whereby overaggressive lymphocyte responses destroy the liver in a continuous and unsuccessful attempt to clear the virus. Unfortunately, we do not know as of yet which of these possibilities is the case and, therefore, a more complete picture of the intrahepatic immune response will be relevant to the development of new therapeutic strategies against HCV. Additionally and from a more general perspective, due to the availability of biopsied material and the high prevalence (approximately 3%) of HCV infection worldwide, studying the chronically inflamed liver of hepatitis C patients is an ideal model to investigate the poorly understood processes of lymphocyte trafficking, activation and death to non-lymphoid sites of chronic inflammation in man.

Adult↗

PubMed2006

Transcriptional profiling of Epstein-Barr virus (EBV) genes and host cellular genes in nasal NK/T-cell lymphoma and chronic active EBV infection.

Nasal NK/T-cell lymphoma is an aggressive subtype of non-Hodgkin lymphoma (NHL) that is closely associated with Epstein-Barr virus (EBV). The clonal expansion of EBV-infected NK or T cells is also seen in patients with chronic active EBV (CAEBV) infection, suggesting that two diseases might share a partially similar mechanism by which EBV affects host cellular gene expression. To understand the pathogenesis of EBV-associated NK/T-cell lymphoproliferative disorders (LPD) and design new therapies, we employed a novel EBV DNA microarray to compare patterns of EBV expression in six cell lines established from EBV-associated NK/T-cell LPD. We found that expression of BZLF1, which encodes the immediate-early gene product Zta, was expressed in SNK/T cells and the expression levels were preferentially high in cell lines from CAEBV infection. We also analyzed the gene expression patterns of host cellular genes using a human oligonucleotide DNA microarray. We identified a subset of pathogenically and clinically relevant host cellular genes, including TNFRSF10D, CDK2, HSPCA, IL12A as a common molecular biological properties of EBV-associated NK/T-cell LPD and a subset of genes, such as PDCD4 as a putative contributor for disease progression. This study describes a novel approach from the aspects of viral and host gene expression, which could identify novel therapeutic targets in EBV-associated NK/T-cell LPD.

Chronic Disease↗

PubMed2003

Perforin is required for innate and adaptive immunity induced by heat shock protein gp96.

Tumor-secreted gp96-Ig is highly immunogenic and triggers CD8 T cell-mediated tumor rejection. In vivo secreted gp96-Ig and gp96-myc cause NK activation and clonal expansion of specific CD8(+) CTL in wild-type and in Fas-ligand-deficient (gld) mice but not in perforin- (PKO) or IFN-gamma-deficient (GKO) mice. Transfer of perforin-competent NK cells restores the ability of PKO mice to clonally expand CD8 CTL in response to gp96-Ig. The data demonstrate an essential role for perforin-mediated functions in the activation of innate and adaptive immunity by heat shock protein gp96-peptide complexes. Crosspresentation of antigens by heat shock proteins seems to require a perforin-dependent positive feedback loop between NK and DC for both sustained NK activation and clonal CTL expansion. The studies also explain how depressed NK activity in patients with tumors or after viral infections could diminish CTL responses.

Adoptive Transfer↗

PubMed1987

Fine analysis of cytolytic and natural killer T lymphocytes in the CSF in multiple sclerosis and other neurologic diseases.

Cytolytic T lymphocyte precursors (CTL-p) and natural killer precursors (NK-p) in the CSF of 15 MS patients and 11 patients with other neurologic disorders (OND) were quantitatively assessed, using a T-lymphocyte microculture system that allows clonal expansion of all human T cells. CSF CTL-p and NK-p frequencies were higher in patients with OND of inflammatory nature than in patients with noninflammatory OND. In all MS patients, these frequencies were higher in the CSF than in their peripheral blood. Surprisingly, in all patients studied, the CSF contained a substantial number of CTL-p with a helper (CD4+) phenotype.

Humans↗

PubMed1987

Rearrangement for the T-cell receptor gene and co-expression of immature T-cell markers and natural killer cell phenotype, in a patient with acute lymphoblastic leukaemia.

We describe a patient with acute lymphoblastic leukaemia whose blasts co-expressed immature T-cell markers and nearly the entire phenotypic repertoire of NK cells. The T-cell nature of the proliferating blasts was proven by the demonstration of the rearrangement for the beta-chain of the T-cell antigen receptor. Although an abnormal phenotypic expression related to the neoplastic proliferation cannot be formally excluded, it is possible that the cells in this patient may represent the clonal expansion of a normal subpopulation of T-cell lineage NK-related cells frozen at an early stage of differentiation. These features provide arguments for discussing the controversial issue of the ontogeny of NK cells and their relationship to the T-cell lineage.

Acute Disease↗

PubMed1991

Patterns of CD16 and CD56 expression in persistent expansions of CD3+NKa+ lymphocytes are predictive for clonal T-cell receptor gene rearrangements. The Yorkshire Leukaemia Group.

Phenotypic characteristics, and correlations between the expression of membrane NK-associated (NKa) determinants (CD11b, CD16, CD56 and CD57) and T cell receptor (TCR) genotypic patterns, were examined in 25 patients with persistent (greater than 6 months) expansions of CD3+WT31+NKa+ (CD8+ and CD8dim+) lymphocytes. These studies showed that distinct NKa phenotypic profiles were restricted to cases with rearranged TCR configurations and that clonal CD3+NKa+ components could be predicted in most cases by assessing relationships between membrane CD16 and CD56 expression. For all normal NKa subpopulations, there was a high correlation (P less than 0.0001; n = 31) between the expression of these two membrane determinants. Markedly increased CD16 expression by CD3+NKa+ cells, in relation to CD56 (i.e. a high CD16:CD56 ratio), was found exclusively in cases with rearranged TCR (13/16 cases); 2/3 of the remaining cases showing significantly reduced CD16:CD56 ratios and high (greater than 2.0) CD3+CD56+ absolute numbers. In contrast, 7/9 of the germline TCR cases had a normal CD16:CD56 ratio and 2/9 a decreased ratio with low (less than 1.0) CD3+CD56+ absolute numbers. A high ratio of CD16:CD56 expression by CD3+NKa+ lymphocytes was therefore informative for 82% of TCR rearrangements in this series; and analysis of CD16 and CD56 expression was predictive for germline and rearranged TCR configurations in 24/25 persistent CD3+NKa+ expansions.

Adult↗

PubMedDate not supplied

Pathogenesis of chronic active Epstein-Barr virus infection: is this an infectious disease, lymphoproliferative disorder, or immunodeficiency?

Chronic active Epstein-Barr virus infection (CAEBV) is characterised by chronic or recurrent infectious mononucleosis-like symptoms, such as fever, hepatosplenomegaly, persistent hepatitis and extensive lymphadenopathy. Patients with CAEBV have high viral loads in their peripheral blood and/or an unusual pattern of EBV-related antibodies. This disease is rare but severe with high morbidity and mortality. Nearly three decades have passed since this disease was first identified, and recent advances in technology have increased our understanding of CAEBV pathophysiology. There is accumulating evidence that the clonal expansion of EBV-infected T or natural killer (NK) cells plays a central role in the pathogenesis of CAEBV. However, it remains unclear whether CAEBV is truly a monoclonal lymphoproliferative disorder. EBV-infected T or NK cells are able to evade the host cellular immune system due to the limited expression of viral proteins of reduced antigenicity. Recent studies suggest that infection of T or NK cells is a common event during primary EBV infection. A defect or single nucleotide polymorphism in host immune-modulating genes may allow for the expansion of virus infected cells giving rise to CAEBV. In this review, I summarise our current understanding of the pathogenesis of CAEBV and propose a model of CAEBV pathogenicity.

Epstein-Barr Virus Infections↗