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PubMed2000

Memory B cells and CD27.

Following antigen activation in germinal centers, B cells develop into memory B cells or plasma cells. Triggering via B-cell immunoglobulin receptors by antigens, cytokines and direct cell-to-cell contact by B and T cells plays an important role in the B cell differentiation into memory or plasma cells. Adult human peripheral blood B cells are separated into three subtypes by the expression of IgD and CD27, which belong to the tumor necrosis factor receptor (TNFR) family: IgD+ CD27- naive B cells, IgD+ CD27+ and IgD- CD27+ B cells. CD27+ B cells are larger cells with abundant cytoplasm carrying somatic hypermutation, and have an ability to produce immunoglobulin, indicating that CD27 is a memory marker of B cells. The ligation of CD27 yields crucial signals that positively control the entry of B cells into the pathway to plasma cells. We review observations on subpopulations and differentiation of mature B-cells by T/B cell interaction via CD27/CD70 as compared with CD40/CD154 interaction, and discuss about memory B cells.

Adult↗
PubMed2005

Spontaneous and homeostatic proliferation of CD4 T cells are regulated by different mechanisms.

Transfer of naive CD4 T cells into lymphopenic mice initiates a proliferative response of the transferred cells, often referred to as homeostatic proliferation. Careful analysis reveals that some of the transferred cells proliferate rapidly and undergo robust differentiation to memory cells, a process we have designated spontaneous proliferation, and other cells proliferate relatively slowly and show more limited evidence of differentiation. In this study we report that spontaneous proliferation is IL-7 independent, whereas the slow proliferation (referred to as homeostatic proliferation) is IL-7 dependent. Administration of IL-7 induces homeostatic proliferation of naive CD4 T cells even within wild-type recipients. Moreover, the activation/differentiation pattern of the two responses are clearly distinguishable, indicating that different activation mechanisms may be involved. Our results reveal the complexity and heterogeneity of lymphopenia-driven T cell proliferation and suggest that they may have fundamentally distinct roles in the maintenance of CD4 T cell homeostasis.

Adoptive Transfer↗
PubMed2004

Declarative memory after stress in humans: differential involvement of the beta-adrenergic and corticosteroid systems.

To determine the role played by the beta-adrenergic and corticosteroid systems in the modulatory effects of stress on declarative memory function, 42 young men were administered a placebo, propranolol (beta-adrenergic blocker), or metyrapone (corticosteroid synthesis inhibitor) before being submitted to a psychological stress protocol. Immediately after stress, subjects viewed a neutral story, unrelated to the stressor. Short- (5 min post learning) and long-term (1 wk post learning) recall of the story was assessed. Placebo and propranolol groups showed significant stress-related increases in corticosteroid levels, whereas metyrapone prevented corticosteroid reactivity to the stressor. Stress triggered significant elevations in cardiac activity (heart rate, systolic and diastolic blood pressure levels) in all three groups, with the metyrapone group showing the strongest elevation in heart rate levels in response to stress. Compared with placebo, propranolol had no effect on short- and long-term recall of the story learned after stress, whereas metyrapone impaired short-term recall of the story, with no further effects on long-term declarative memory. These results suggest that, contrary to the beta-adrenergic system, the corticosteroid system is implicated in declarative memory function after stress in humans.

Adolescent↗
PubMed2003

Prolonged presence of effector-memory CD8 T cells in the central nervous system after dengue virus encephalitis.

Dengue virus infection in the central nervous system (CNS) of immunized mice results in a strong influx of CD8 T cells into the brain. Whereas the kinetics of the splenic antiviral response are conventional, i.e. expansion followed by a rapid drop in the frequency of specific CD8 T cells, dengue virus-specific CD8 T cells are retained in the CNS at a high frequency. These CD8 T cells display a partially activated phenotype (CD69(high), Ly-6A/E(high), CD62L(low)), characteristic for effector-memory T cells. CD43 expression, visualized by staining with the 1B11 mAb, decreased in time, suggesting that these persisting CD8 T cells differentiated into memory cells. These data add to the growing evidence implicating the CNS as a non-lymphoid tissue capable of supporting prolonged T cell survival/maintenance.

Animals↗
PubMed2000

Distinct role of follicular dendritic cells and T cells in the proliferation, differentiation, and apoptosis of a centroblast cell line, L3055.

Germinal center (GC) B cells undergo complex interactions with follicular dendritic cells (FDC) and T cells in the course of differentiation into memory B and plasma cells. To delineate the individual roles of FDC and T cells at each stage of GC B cell differentiation at the clonal level and to analyze the signals involved, we adopted a unique experimental model using an FDC line, HK, and a lymphoma cell line, L3055, that resembles centroblasts. A detailed phenotypic analysis revealed L3055 cells to be a clonal population originating from the GC. Like freshly isolated centroblasts, L3055 cells underwent spontaneous apoptosis when cultured in the absence of fresh FDC or HK cells. L3055 cells proliferated continuously in the presence of HK cells, while they differentiated into a population with the phenotype of centrocytes after stimulation with CD40 ligand (CD40L) and IL-4. The CD40L-stimulated L3055 cells underwent CD95-mediated apoptosis, which was reminiscent of the feature of CD40L-stimulated tonsillar GC B cells. In contrast to HK cells that did not protect L3055 cells from anti-Ig killing, CD40L plus IL-2, IL-4, and IL-10 prevented anti-Ig-induced apoptosis. These experimental results demonstrate a distinct function of FDC and activated T cells, in that FDC provide signals for rapid proliferation of centroblasts, whereas T cells confer signals for differentiation of centroblasts into centrocytes and resistance to B cell receptor-mediated apoptosis. T cells collaborate with FDC in the protection and expansion of the Ag-specific GC B cells.

Adolescent↗
PubMed1995

Human naive and memory T lymphocytes differ in telomeric length and replicative potential.

The present study has assessed the replicative history and the residual replicative potential of human naive and memory T cells. Telomeres are unique terminal chromosomal structures whose length has been shown to decrease with cell division in vitro and with increased age in vivo for human somatic cells. We therefore assessed telomere length as a measure of the in vivo replicative history of naive and memory human T cells. Telomeric terminal restriction fragments were found to be 1.4 +/- 0.1 kb longer in CD4+ naive T cells than in memory cells from the same donors, a relationship that remained constant over a wide range of donor age. These findings suggest that the differentiation of memory cells from naive precursors occurs with substantial clonal expansion and that the magnitude of this expansion is, on average, similar over a wide range of age. In addition, when replicative potential was assessed in vitro, it was found that the capacity of naive cells for cell division was 128-fold greater as measured in mean population doublings than the capacity of memory cells from the same individuals. Human CD4+ naive and memory cells thus differ in in vivo replicative history, as reflected in telomeric length, and in their residual replicative capacity.

Adult↗
PubMedDate not supplied

Changes in memory and naive CD4+ lymphocytes in lymph nodes and spleen after thermal injury.

T cells expressing CD4 can be further subdivided by their expression of CD45R. In humans, CD45RO+ cells function as memory T cells, and CD4+CD45RA+ function as naive T cells, i.e., cells that have never previously encountered antigen. In the rat, similar functional division of CD4 cells can be made with antibody OX-22 (anti-CD45RC) with CD4+CD45RC- and CD4+CD45RC+ identifying the memory and naive phenotypes respectively. With use of the rat model, we studied the effect of burn injury on CD4 cell subpopulations and memory and naive T cells in lymph nodes draining the burn wound (NDB) and spleen. In the NDB we found that numbers of memory and naive CD4 cells increased significantly as a function of time after burn injury, and that this increase was greater for naive cells (5.7-fold) than for memory cells (4.1-fold). However, in the spleen, we found memory T-cell numbers decreased significantly on postburn days 12 and 18, whereas naive CD4 cells in the spleen manifested no changes at any time after burn. These results may be explained by the different trafficking patterns of memory and naive cells. Based on the cell surface marker, L-selectin, naive cells preferentially migrate into the NDB where they undergo differentiation into memory cells. Memory cells selectively migrate into inflamed burned tissue, which may account for their lesser-fold increase in NDB when compared to naive cells, and their decreased numbers in the spleen after burn injury.

Analysis of Variance↗
PubMed2005

Cytomegalovirus-specific CD4+ T cells in healthy carriers are continuously driven to replicative exhaustion.

Repeated antigenic encounter drives proliferation and differentiation of memory T cell pools. An important question is whether certain specific T cells may be driven eventually to exhaustion in elderly individuals since the human life expectancy is increasing. We found that CMV-specific CD4+ T cells were significantly expanded in healthy young and old carriers compared with purified protein derivative-, varicella zoster virus-, EBV-, and HSV-specific populations. These CMV-specific CD4+ T cells exhibited a late differentiated phenotype since they were largely CD27 and CD28 negative and had shorter telomeres. Interestingly, in elderly CMV-seropositive subjects, CD4+ T cells of different specificities were significantly more differentiated than the same cells in CMV-seronegative individuals. This suggested the involvement of bystander-secreted, differentiation-inducing factors during CMV infection. One candidate was IFN-alpha, which induced loss of costimulatory receptors and inhibited telomerase in activated CD4+ T cells and was secreted at high levels by CMV-stimulated plasmacytoid dendritic cells (PDC). The CMV-specific CD4+ T cells in elderly subjects had severely restricted replicative capacity. This is the first description of a human memory T cell population that is susceptible to being lost through end-stage differentiation due to the combined effects of lifelong virus reactivation in the presence of bystander differentiation-inducing factors.

Adult↗
PubMed1997

Memory B cells are biased towards terminal differentiation: a strategy that may prevent repertoire freezing.

Isolation of large numbers of surface IgD+CD38- naive and surface IgD-CD38- memory B cells allowed us to study the intrinsic differences between these two populations. Upon in vitro culture with IL-2 and IL-10, human CD40-activated memory B cells undergo terminal differentiation into plasma cells more readily than do naive B cells, as they give rise to five- to eightfold more plasma cells and three- to fourfold more secreted immunoglobulins. By contrast, naive B cells give rise to a larger number of nondifferentiated B blasts. Saturating concentrations of CD40 ligand, which fully inhibit naive B cell differentiation, only partially affect that of memory B cells. The propensity of memory B cells to undergo terminal plasma cell differentiation may explain the extensive extra follicular plasma cell reaction and the limited germinal center reaction observed in vivo after secondary immunizations, which contrast with primary responses in carrier-primed animals. This unique feature of memory B cells may confer two important capacities to the immune system: (a) the rapid generation of a large number of effector cells to efficiently eliminate the pathogens; and (b) the prevention of the overexpansion and chronic accumulation of one particular memory B cell clone that would freeze the available peripheral repertoire.

Animals↗
PubMed2004

IL-2 production by virus- and tumor-specific human CD8 T cells is determined by their fine specificity.

Memory CD8 T cells mediate rapid and effective immune responses against previously encountered Ags. However, these cells display considerable phenotypic and functional heterogeneity. In an effort to identify parameters that correlate with immune protection, we compared cell surface markers, proliferation, and cytokine production of distinct virus- and tumor-specific human CD8 populations. Phenotypic analysis of epitope-specific CD8 T cells showed that Ag specificity is associated with distinct CCR7/CD45RA expression profiles, suggesting that Ag recognition drives the expression of these molecules on effector/memory T cells. Moreover, the majority of central memory T cells (CD45RAlowCCR7dull) secreting cytokines in response to an EBV epitope produces both IL-2 and IFN-gamma, whereas effector memory CD8 cells (CD45RAdullCCR7-) found in EBV, CMV, or Melan-A memory pools are mostly composed of cells secreting exclusively IFN-gamma. However, these various subsets, including Melan-A-specific effector memory cells differentiated in cancer patients, display similar Ag-driven proliferation in vitro. Our findings show for the first time that human epitope-specific CD8 memory pools differ in IL-2 production after antigenic stimulation, although they display similar intrinsic proliferation capacity. These results provide new insights in the characterization of human virus- and tumor-specific CD8 lymphocytes.

Antigens, Neoplasm↗
PubMed1997

The cellular origins of memory B cells.

Recent evidence indicates that memory B cells may originate from a precursor cell subset that is distinct from AFC precursors. Most convincing is the finding that fractionation of naive peripheral B-cell populations on the basis of surface heat stable antigen (HSA) expression yields two populations; one greatly enriched for progenitors of memory B cells (HSAlo), and the other enriched for AFC precursors (HSAint-hi). Antigenic stimulation of HSAlo B cells in vitro leads to the generation of memory B-cell clones in the absence of any detectable antibody formation whereas stimulation of HSAint-hi cells yield AFC responses but not memory B cells. Furthermore, the progeny of HSAlo cells are unique in their ability to accumulate somatic mutations and originate germinal centers (GC). The pre-existence of two distinct precursor cell populations may help resolve the disparate biological characteristics of AFC precursors which appear to be terminally differentiated versus memory progenitors which retain stem cell characteristics in their capacity to self renew, undergo multiple divisions, and generate progeny that express enzymes characteristic of stem cells or pro-pre B cells and acquire tolerance susceptibility.

Animals↗
PubMed1996

Centrocytes rapidly adopt a memory B cell phenotype on co-culture with autologous germinal centre T cell-enriched preparations.

B cells, after mutating their Ig B-region genes in germinal centres (GC), undergo apoptosis, unless they receive antigen-dependent selection signals. The signals appear to be delivered by GC T cells, require CD40 ligand expression and may induce differentiation to memory cells. Cultured GC B cells are prevented from entering apoptosis by ligating their surface CD40, but the resulting phenotype is not associated with B cells found in vivo. Conversely, GC B cells rapidly adopt a memory B cell phenotype on culture with autologous memory CD4(+) T cells that have been induced to express CD40 ligand transiently. This effect is prevented by blocking CD40 ligand. Naive CD4(+) T cells, induced to express CD40 ligand, do not prevent GC B cells undergoing apoptosis.

Adolescent↗
PubMed2004

Facial recognition deficits and cognition in schizophrenia.

Previous investigations have found impaired recognition of facial affect and cognition in schizophrenia. We compared patients with schizophrenia and healthy control volunteers on computerized tasks of emotion recognition, to determine whether emotion processing deficits were correlated with neurocognitive performance. A Computerized Neuropsychological Test Battery (CNP) was administered to 40 patients (25 male, 15 female, mean age+/-S.D. 30.4+/-8.1) with schizophrenia (DSM-IV, 15 first episode and 25 chronically ill patients) treated with atypical neuroleptics and 43 healthy volunteers. A German version of the PENN Facial Discrimination, Differentiation and Memory Test, including happy, sad and neutral faces was used. Additionally, all patients were tested with a standard neuropsychological battery and rated for positive and negative symptoms. Patients with schizophrenia performed worse than control subjects on all emotion recognition tasks (p<0.01). We found higher error rates for discrimination of emotion in happy (p<0.02) and happy female faces (p<0.01), for differentiation of sad versus happy faces (p<0.001) and for facial memory (p<0.04). Poorer performance in emotion discrimination and facial memory correlated with severity of negative symptoms, abstraction-flexibility (p<0.001), verbal memory (p<0.01) and language processing (p<0.001). The study did not reveal a specific deficit for emotion recognition in schizophrenia. These findings lend support to the notion that difficulties in emotion recognition are associated in schizophrenia with key cognitive deficits.

Adult↗
PubMed2006

miR-7b, a microRNA up-regulated in the hypothalamus after chronic hyperosmolar stimulation, inhibits Fos translation.

The transcription factor activator protein 1 (AP-1) is formed through the dimerization of immediate-early genes Fos and Jun family members. Activator protein 1 is known as a pivotal regulator of major biological events such as cell proliferation, differentiation, organogenesis, memory formation, and apoptosis. During a search for microRNAs (miRNAs; small, endogenous, noncoding RNAs that repress gene expression of target mRNAs in animals posttranscriptionally) that are differentially expressed in the mouse paraventricular and supraoptic nuclei after 10 days of drinking 2% saline, one candidate microRNA that is relatively highly expressed, mmu-miR-7b (miR-7b), was studied further because sequence analysis suggested a likely interaction with the 3' untranslated region of Fos mRNA. We show that miR-7b expression inhibits Fos translation in vitro and that it and its host gene are prominently expressed in the PVN and other brain areas, including the suprachiasmatic nucleus. No effect on Fos mRNA levels was observed. Normally, Fos is expressed at low to undetectable levels in cells, but it shows rapid induction and decay after acute stimuli. Various pathways have been identified through which Fos family proteins are degraded; our results indicate a significant additional mechanism by which Fos protein and activity may be regulated.

3' Untranslated Regions↗
PubMed1983

Age-related changes in confusion between memories for thoughts and memories for speech.

The present experiments compared people's abilities to make decisions about the origin of their memories. Experiment 1 demonstrated that 6-year-olds were as good as 17-year-olds in discriminating memories originating from what they said earlier (self-generations) from memories of what another person said earlier (external presentations). However, in both experiments 1 and 2, 6-year-olds were not as good at discriminating what they had said earlier from what they had only thought. The possibility that younger children simply have more difficulty distinguishing between memories originating from the same class, internal or external, was ruled out because 6-year-olds performed as well as 9-year-olds when differentiating between memories from 2 external sources (experiment 2). Nor could their difficulty be attributed to a general problem in distinguishing memories for their thoughts from any other class of memories because they were at no disadvantage in discriminating their earlier thoughts (words they imagined themselves saying) from words someone else said (experiment 2). Our findings suggest that some distinctions, self versus other, emerge as cues in memory sooner than other distinctions, thoughts versus actions.

Adolescent↗
PubMed2006

Early gamma interferon and interleukin-2 responses to vaccination predict the late resting memory in malaria-naïve and malaria-exposed individuals.

Two different cell populations respond to potent T-cell-inducing vaccinations. The induction and loss of effector cells can be seen using an ex vivo enzyme-linked immunospot (ELISPOT) assay, but the more durable resting memory response is demonstrable by a cultured ELISPOT assay. The relationship of the early effector response to durable resting memory is incompletely understood. Effector phenotype is usually identified by gamma interferon (IFN-gamma) production, but interleukin-2 (IL-2) has been specifically linked to the differentiation of memory cells. Here, IFN-gamma- and IL-2-secreting effector cells were identified by an ex vivo ELISPOT assay 1 week after vaccination and compared with the resting memory responses detected by a cultured ELISPOT assay 3 months later. The different kinetics and induction of IL-2 by different vaccines and natural exposure are described. Furthermore, both early IFN-gamma and IL-2 production independently predicted subsequent memory responses at 3 months in malaria-naïve volunteers, but only IFN-gamma predicted memory in malaria-exposed volunteers. However, dual ELISPOT assays were also performed on malaria-exposed volunteers to identify cells producing both cytokines simultaneously. This demonstrated that double-cytokine-producing cells were highly predictive of memory. This assay may be useful in predicting vaccinations most likely to generate stable, long-term memory responses.

Animals↗
PubMed2005

Terminal differentiation into plasma cells initiates the replicative cycle of Epstein-Barr virus in vivo.

In this paper we demonstrate that the cells which initiate replication of Epstein-Barr virus (EBV) in the tonsils of healthy carriers are plasma cells (CD38hi, CD10-, CD19+, CD20lo, surface immunoglobulin negative, and cytoplasmic immunoglobulin positive). We further conclude that differentiation into plasma cells, and not the signals that induce differentiation, initiates viral replication. This was confirmed by in vitro studies showing that the promoter for BZLF1, the gene that begins viral replication, becomes active only after memory cells differentiate into plasma cells and is also active in plasma cell lines. This differs from the reactivation of BZLF1 in vitro, which occurs acutely and is associated with apoptosis and not with differentiation. We suggest that differentiation and acute stress represent two distinct pathways of EBV reactivation in vivo. The fraction of cells replicating the virus decreases as the cells progress through the lytic cycle such that only a tiny fraction actually release infectious virus. This may reflect abortive replication or elimination of cells by the cellular immune response. Consistent with the later conclusion, the cells did not down regulate major histocompatibility complex class I molecules, suggesting that this is not an immune evasion tactic used by EBV and that the cells remain vulnerable to cytotoxic-T-lymphocyte attack.

Antigens, CD20↗
PubMed2003

Maintenance of long term gamma-herpesvirus B cell latency is dependent on CD40-mediated development of memory B cells.

It has been proposed that the gamma-herpesviruses maintain lifelong latency in B cells by gaining entry into the memory B cell pool and taking advantage of host mechanisms for maintaining these cells. We directly tested this hypothesis by kinetically monitoring viral latency in CD40(+) and CD40(-) B cells from CD40(+)CD40(-) mixed bone marrow chimera mice after infection with a murine gamma-herpesvirus, MHV-68. CD40(+) B cells selectively entered germinal centers and differentiated into memory B cells. Importantly, latency was progressively lost in the CD40(-) B cells and preferentially maintained in the long-lived, isotype-switched CD40(+) B cells. These data directly demonstrate viral exploitation of the normal B cell differentiation pathway to maintain latency.

3T3 Cells↗