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At least 325 records · Page 18Linked to original sources
PubMed2005

Virus-specific cytotoxic T lymphocytes differentially express cell-surface leukocyte immunoglobulin-like receptor-1, an inhibitory receptor for class I major histocompatibility complex molecules.

Leukocyte immunoglobulin-like receptor-1 (LIR-1) is an inhibitory receptor that negatively regulates T cell effector functions after interaction with host class I major histocompatibility complex molecules and, additionally, binds to UL18, a human cytomegalovirus (HCMV)-encoded class I homologue. Here, we demonstrate that virus-specific cytotoxic T lymphocytes (CTLs) differentially express LIR-1, with high frequencies of expression on HCMV-specific CD8+ T cells and intermediate and low frequencies of expression on influenza virus-specific and Epstein-Barr virus (EBV)-specific CTLs, respectively. Expression of LIR-1 was dependent on CTL-antigen specificity and was associated with a differentiated effector memory phenotype, as demonstrated by decreased expression of CD28 and increased expression of CD57. During primary HCMV and EBV infections, expression of LIR-1 on virus-specific CTLs was low and increased slowly. These results indicate that expression of LIR-1 increases during differentiation of virus-specific CD8+ effector T cells. Furthermore, they suggest that a potential immunoregulatory function of UL18 may be to preferentially target highly differentiated HCMV-specific effector memory T cells during persistent infection.

Antigens, CD↗
PubMed2007

Chemokine-guided CD4+ T cell help enhances generation of IL-6RalphahighIL-7Ralpha high prememory CD8+ T cells.

CD4(+) T cells promote effective CD8(+) T cell-mediated immunity, but the timing and mechanistic details of such help remain controversial. Furthermore, the extent to which innate stimuli act independently of help in enhancing CD8(+) T cell responses is also unresolved. Using a noninfectious vaccine model in immunocompetent mice, we show that even in the presence of innate stimuli, CD4(+) T cell help early after priming is required for generating an optimal pool of functional memory CD8(+) T cells. CD4(+) T cell help increased the size of a previously unreported population of IL-6Ralpha(high)IL-7Ralpha(high) prememory CD8(+) T cells shortly after priming that showed a survival advantage in vivo and contributed to the majority of functional memory CD8(+) T cells after the contraction phase. In accord with our recent demonstration of chemokine-guided recruitment of naive CD8(+) T cells to sites of CD4(+) T cell-dendritic cell interactions, the generation of IL-6Ralpha(high)IL-7Ralpha(high) prememory as well as functional memory CD8(+) T cells depended on the early postvaccination action of the inflammatory chemokines CCL3 and CCL4. Together, these findings support a model of CD8(+) T cell memory cell differentiation involving the delivery of key signals early in the priming process based on chemokine-guided attraction of naive CD8(+) T cells to sites of Ag-driven interactions between TLR-activated dendritic cells and CD4(+) T cells. They also reveal that elevated IL-6Ralpha expression by a subset of CD8(+) T cells represents an early imprint of CD4(+) T cell helper function that actively contributes to the survival of activated CD8(+) T cells.

Animals↗
PubMed2006

Mathematically modeling dynamics of T cell responses: predictions concerning the generation of memory cells.

Mathematical models of T cell population dynamics after infection typically assume that T cells differentiate according to a linear process in which they first become effector cells, and then after some time, differentiate further into memory cells. In this paper, we offer a different mathematical model which can equally well capture T cell dynamics, using data from lymphocytic choriomeningitis (LCMV) infection. Our model assumes that memory cells are intermediates that further differentiate into effector cells only from additional or stronger antigenic stimulation. Our assumption naturally leads to a testable prediction about the generation of T cell memory-that the memory phenotype of T cells should be present in detectable numbers during the expansion phase of the response. We use our model to estimate a rate of differentiation from memory type cells to effectors. We argue that this differentiation assumption, where memory cells are intermediates, captures recent experimental work on T cell differentiation, and hence this new mathematical model could be helpful in doing further studies of T cell population dynamics. We also propose a method of distinguishing the models by examining the ratio of memory T cells detectable long after an infection to the peak numbers of T cells at the end of the expansion phase.

CD4-Positive T-Lymphocytes↗
PubMed2005

IL-21 induces differentiation of human naive and memory B cells into antibody-secreting plasma cells.

IL-21 is a type I cytokine that influences the function of T cells, NK cells, and B cells. In this study, we report that IL-21 plays a major role in stimulating the differentiation of human B cells. When human B cells were stimulated through the BCR, IL-21 induced minimal proliferation, IgD down-modulation, and small numbers of plasma cells. In contrast, after CD40 engagement, IL-21 induced extensive proliferation, class switch recombination (CSR), and plasma cell differentiation. Upon cross-linking both BCR and CD40, IL-21 induced the largest numbers of plasma cells. IL-21 drove both postswitch memory cells as well as poorly responsive naive cord blood B cells to differentiate into plasma cells. The effect of IL-21 was more potent than the combination of IL-2 and IL-10, especially when responsiveness of cord blood B cells was examined. IL-21 costimulation potently induced the expression of both B lymphocyte-induced maturation protein-1 (BLIMP-1) and activation-induced cytidine deaminase as well as the production of large amounts of IgG from B cells. Despite the induction of activation-induced cytidine deaminase and CSR, IL-21 did not induce somatic hypermutation. Finally, IL-2 enhanced the effects of IL-21, whereas IL-4 inhibited IL-21-induced plasma cell differentiation. Taken together, our data show that IL-21 plays a central role in CSR and plasma cell differentiation during T cell-dependent B cell responses.

Antibody Formation↗
PubMed2004

Serine protease inhibitor 2A is a protective factor for memory T cell development.

An essential event in the development of memory CD8(+) T lymphocytes is the escape of progenitors from programmed cell death, but how this is mediated is unclear. Here we report that the gene encoding serine protease inhibitor 2A (Spi2A), an inhibitor of lysosomal executioner proteases dependent on transcription factor NF-kappaB, is upregulated in memory cell precursors. Spi2A upregulation protected lymphocytic choriomeningitis virus-specific memory progenitors from programmed cell death. Thus, Spi2A promotes the survival of cytotoxic T lymphocytes, allowing them to differentiate into memory CD8 T cells. These findings suggest a model in which commitment to the memory lineage is facilitated by the upregulation of protective genes.

Animals↗
PubMed2001

Arrested differentiation, the self-renewing memory lymphocyte, and vaccination.

Vaccination for persistent viral or bacterial infections must program the immune system for a lifelong need to generate antigen-specific effector lymphocytes. How the immune system does this is not known, but recent studies have shown that a subset of B lymphocytes, the germinal center B cell, is capable of self-renewal because it expresses a transcriptional repressor, BCL6, that blocks terminal differentiation. If a similar mechanism for arresting differentiation exists for long-lived, antigen-selected lymphocytes, a stem cell-like capacity for self-renewal could be the basis for the continual generation of effector lymphocytes from the memory pool. Understanding how to regulate the terminal differentiation of lymphocytes will improve immunotherapeutic approaches for chronic infectious diseases and cancer.

Animals↗
PubMed1999

Further characterization of memory T cells existing in a case of CD8 deficiency.

CD8 deficiency is a rare primary immunodeficiency caused by a defect of ZAP-70, which plays a pivotal role in T cell activation. We previously reported the existence of memory phenotype-CD4+ T cells in a case of CD8 deficiency, which demonstrates that activation signals through ZAP-70 are not essential to the phenotypic conversion of T cells from "naive" to "memory." In this study, we further characterized CD45RO+ T cells in a CD8 deficient patient. We showed that the patient's CD45RO+ T cell population had a wide variety of T cell receptor Vbeta-chain gene usage, and contained few clonally expanded T cells, while many clonally expanded T cells were present in the memory T cell population of age-matched healthy children. These results suggest that various kinds of antigens were involved in the differentiation of the patient's T cells, and that the differentiation into memory T cells was not accompanied by profound T cell proliferation. Moreover, our findings confirmed that the patient's CD45RO+CD4+ T cells had acquired effector-cytokine producing ability, indicating that there exists an alternative activation pathway which is independent of ZAP-70 for the acquisition of effector-cytokine producing ability.

CD8 Antigens↗
PubMed1988

Differential activation requirements for virgin and memory T cells.

Most studies of the activation requirements for T cells have used either T cell lines or populations of normal T cells that consist of a mixture of virgin and Ag-primed T cells. These two subpopulations of T cells can now be distinguished in humans by their reactivity with mAb. The anti-CD45R antibody HB10 identifies virgin T cells (T degrees) that are non-reactive to recall Ag and relatively poor at providing help for B cell differentiation. Conversely, memory T cells (T') that can react to recall Ag and enhance Ig production are non-reactive with anti-CD45R, but can be identified with the UCHL1 antibody. We have used these antibodies to separate the T degrees and T' populations and examine their activation requirements. On activation CD45R+ cells rapidly began to lose the CD45R Ag and express the UCHL1 Ag in increased amounts, whereas the UCHL1+ cells retained this phenotype. Both populations responded to PHA in the presence of monocytes, but when triggered by an antibody to CD3 only the T' cells were induced to express IL-2R, produce IL-2, and to proliferate. The T degrees population of cells remained relatively quiescent by all of these parameters. However, anti-CD3 stimulation conditioned the T degrees cells for IL-2 responsiveness, inasmuch as the addition of rIL-2 resulted in significant IL-2R expression and proliferation. When the CD4+ T degrees and CD4+ T' subpopulations were isolated and examined in the same assays similar results were obtained. The data indicate that fundamental differences exist in the triggering requirements for T degrees and T' cells.

Adult↗
PubMed2005

Design of PAP-1, a selective small molecule Kv1.3 blocker, for the suppression of effector memory T cells in autoimmune diseases.

The lymphocyte K+ channel Kv1.3 constitutes an attractive pharmacological target for the selective suppression of terminally differentiated effector memory T (TEM) cells in T cell-mediated autoimmune diseases, such as multiple sclerosis and type 1 diabetes. Unfortunately, none of the existing small-molecule Kv1.3 blockers is selective, and many of them, such as correolide, 4-phenyl-4-[3-(methoxyphenyl)-3-oxo-2-azapropyl]cyclohexanone, and our own compound Psora-4 inhibit the cardiac K+ channel Kv1.5. By further exploring the structure-activity relationship around Psora-4 through a combination of traditional medicinal chemistry and whole-cell patch-clamp, we identified a series of new phenoxyalkoxypsoralens that exhibit 2- to 50-fold selectivity for Kv1.3 over Kv1.5, depending on their exact substitution pattern. The most potent and "drug-like" compound of this series, 5-(4-phenoxybutoxy)psoralen (PAP-1), blocks Kv1.3 in a use-dependent manner, with a Hill coefficient of 2 and an EC50 of 2 nM, by preferentially binding to the C-type inactivated state of the channel. PAP-1 is 23-fold selective over Kv1.5, 33- to 125-fold selective over other Kv1-family channels, and 500- to 7500-fold selective over Kv2.1, Kv3.1, Kv3.2, Kv4.2, HERG, calcium-activated K+ channels, Na+,Ca2+, and Cl- channels. PAP-1 does not exhibit cytotoxic or phototoxic effects, is negative in the Ames test, and affects cytochrome P450-dependent enzymes only at micromolar concentrations. PAP-1 potently inhibits the proliferation of human TEM cells and suppresses delayed type hypersensitivity, a TEM cell-mediated reaction, in rats. PAP-1 and several of its derivatives therefore constitute excellent new tools to further explore Kv1.3 as a target for immunosuppression and could potentially be developed into orally available immunomodulators.

Animals↗
PubMed2002

Differentiation of human CD8(+) T cells from a memory to memory/effector phenotype.

Previous studies of perforin expression and cytokine production in subsets of peripheral human CD45RA(-)CD8(+) T cells with different CD28/CD27 phenotypes showed that CD28(+)CD45RA(-)CD8(+) and CD27(+)CD45RA(-)CD8(+) T cells have characteristics of memory T cells, whereas CD28(-)CD45RA(-)CD8(+) and CD27(-)CD45RA(-)CD8(+) T cells have characteristics of both memory and effector T cells. However, the differentiation pathway from memory CD8(+) T cells into memory/effector CD8(+) T cells has not been completely clarified. We investigated this differentiation pathway using EBV- and human CMV (HCMV)-specific CD8(+) T cells. Three subsets of CD45RA(-)CD8(+) T cells were observed in both total CD8(+) T cells and EBV- or HCMV-specific CD8(+) T cells: CD27(+)CD28(+), CD27(+)CD28(-), and CD27(-)CD28(-). A significant number of the CD27(-)CD28(+) subset was observed in total CD8 T cells. However, this subset was barely detectable in EBV- or HCMV-specific CD8(+) T cells. Analysis of perforin expression and cytotoxic activity in the first three subsets suggested the following differentiation pathway: CD27(+)CD28(+)CD45RA(-)-->CD27(+)CD28(-)CD45RA(-)-->CD27(-)CD28(-)CD45RA(-). This was supported by the observation that the frequency of CCR5(+) cells and CCR7(+) cells decreased during this sequence. Analysis of CCR5 and CCR7 expression in the CD27(+)CD28(+) memory cell subset demonstrated the presence of three CCR5/CCR7 populations: CCR5(-)CCR7(+), CCR5(+)CCR7(+), and CCR5(+)CCR7(-). These findings suggested the following differentiation pathway: CD27(+)CD28(+)CD45RA(-) (CCR5(-)CCR7(+)-->CCR5(+)CCR7(+)-->CCR5(+)CCR7(-))-->CD27(+)CD28(-)CD45RA(-)-->CD27(-)CD28(-)CD45RA(-). The presence of a CD27(-)CD28(+) subset with a CCR5(+)CCR7(-) phenotype implies a specialized role for this subset in the differentiation of CD8(+) T cells.

CD28 Antigens↗
PubMed1997

Homing of naive and memory T lymphocyte subsets to Peyer's patches, lymph nodes, and spleen.

The specificity and efficiency of extravasation of subsets of memory and naive lymphocytes into organized lymphoid tissues has been the subject of recent controversy, but has not been directly assessed in physiologic systems. Here, we compare the lymphoid organ homing of naive and phenotypically defined memory T cells, focusing on memory subsets differentially expressing the integrin receptor alpha4beta7, which is implicated in homing to mucosal sites. Naive T cells (CD44(low), Thy1+) home to all secondary lymphoid organs. Alpha4beta7(high) memory-phenotype (CD44(high)) T cells home to Peyer's patches as efficiently as naive lymphocytes, whereas alpha4beta7- memory-phenotype T cells are essentially excluded from entry into these mucosal lymphoid organs. In contrast, alpha4beta7- memory-phenotype cells home approximately twice as efficiently as alpha4beta7(high) T cells to peripheral lymph nodes, but only approximately 20% as well as naive T cells. Interestingly, the spleen recruits all three identified subsets with nearly equal efficiency. The relative subset localization is similar 2.5 h after injection and after overnight trafficking, suggesting that memory cells can directly extravasate from blood into Peyer's Patches and lymph nodes. We conclude that subsets of memory T cells defined by patterns of homing receptor expression display differential homing to organized lymphoid tissues, an ability that may facilitate homeostatic interactions and target contributions to specialized regional immune responses.

Animals↗
PubMed1979

Neuropsychological evidence for multiple memory systems.

Neuropsychological data provide strong support for the existence of multiple memory systems. The distinction between short-term memory and long-term memory has been discussed in the experimental literature for some years. More recently it has been argued that the concept of long-term memory is misleading in that it fails to differentiate between semantic memory and episodic/event memory. The independent and selective impairment of multiple memory systems, each with its own functional and structural properties, has been recorded in patients with cerebral lesions and the evidence for impairment of such systems is reviewed. It is argued that the cerebral organization of short-term memory, long-term (non-individual) semantic memory and long-term (individual) event memory is highly differentiated.

Agnosia↗
PubMed1998

The offset of childhood amnesia: memory for events that occurred before age 3.

Adult memory for the events surrounding the birth of a sibling was examined in 69 adults. The authors identified a steep offset for childhood amnesia for this event before the child reaches age 2 1/2 years. The authors also examined the accuracy of information recalled. Although the majority of the answers were accurate, false memories were a consistent feature of the data. Alternative explanations of the authors' data were considered by examining the amount of information an additional 57 adults had about a family birth for which they could have no memory. The pattern of results did not support the view that participants might be unable to differentiate between memories and knowledge about the event.

Adult↗
PubMed2004

Interpretative memories of artworks.

It is well known that memories of self-relevant experiences are reconstructed over time. Artworks often require an elongated period of interpretative meaning-making. Such works were therefore used to study temporal aspects of memory construction. In a longitudinal study, individuals' memories of artworks were examined to explore the idea that only with the passage of time would autobiographical memory and emotion be associated with thematic integration of the artwork memory. We also expected that integrated artwork memories would be more differentiated (in terms of number of details) than memories that were not integrated. Memories of artworks were collected from visitors to an art gallery in person as they left the gallery, and 5 months later in a phone interview. Participants were also asked, at both interviews, whether the memory recollection was associated with an autobiographical memory and with an emotion. Associations among the elements of autobiographical memory, emotion, differentiation, and integrated artwork memories were significant only at the time of the longer-term recollection. The data suggest that, during an incubation period, these elements moved from a state of disconnection to interconnection.

Adolescent↗
PubMed1990

On the differential nature of implicit and explicit memory.

In this article, we report two experiments that provide further evidence concerning the differential nature of implicit and explicit memory. In Experiment 1, subjects first undertook a sentence-verification task. While carrying out this task, half of the subjects were also required to carry out a secondary processing task involving tone monitoring. Twenty-four hours later, the subjects' memory for target items in the sentence-verification task was tested explicitly by means of a recognition task and implicitly by examining the extent to which the items primed fragment completion. Recognition performance was significantly impaired by the imposition of secondary processing demands during the original learning phase. In contrast, fragment completion was completely unaffected by this additional processing, even though substantial priming was observed. In Experiment 2, we examined whether priming in fragment completion is influenced by the nature of repetition during initial learning. Subjects studied a list of target items that were each repeated twice. Half the items were repeated immediately (lag 0) and half were repeated after six intervening items (lag 6). Memory for the items was assessed by recognition and by priming in fragment completion. Recognition was affected by lag, with lag 6 items being recognized better than lag 0 items. However, although significant priming was obtained, the extent of this priming was uninfluenced by lag. These data indicate two additional dimensions along which implicit and explicit memory differ and, furthermore, they support recent conceptualizations of processing differences underlying these two forms of memory.

Adult↗
PubMed2003

Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells.

A major unanswered question is what distinguishes the majority of activated CD8 T cells that die after an acute viral infection from the small fraction (5-10%) that survive to become long-lived memory cells. In this study we show that increased expression of the interleukin 7 receptor alpha-chain (IL-7Ralpha) identifies the effector CD8 T cells that will differentiate into memory cells. IL-7R(hi) effector cells contained increased amounts of antiapoptotic molecules, and adoptive transfer of IL-7R(hi) and IL-7R(lo) effector cells showed that IL-7R(hi) cells preferentially gave rise to memory cells that could persist and confer protective immunity. Thus, selective expression of IL-7R identifies memory cell precursors, and this marker may be useful in predicting the number of memory T cells generated after infection or immunization.

Adoptive Transfer↗
PubMed1979

Detection of memory cells by chemical modification of the lymphocyte cell surface.

Stringent alloantigen requirements, necessary for the differentiation of human memory cells into specific secondary cytolytic T cells (2 degrees CTL), can be bypassed by chemical modification of memory cells with the mitogenic oxidising agent, galactose oxidase. Treatment of memory cells generated in a long-term primary mixed lymphocyte culture with neuraminidase and galactose oxidase (NAGO) results in the differentiation of memory cells into 2 degrees CTL. In contrast, treatment of unprimed cells with NAGO does not result in CTL production despite the proliferation resulting from such treatment.

Cell Membrane↗
PubMed1995

Are rape memories different? A comparison of rape, other unpleasant, and pleasant memories among employed women.

The study examined empirically-measured memory characteristics, compared pleasant and unpleasant intense memories as well as rape and other unpleasant memories, and determined whether rape memories exhibited significantly more "flashbulb" characteristics. Data consisted of responses to a mailed survey of women employees of a medical center (N = 1,037) and a university (N = 2,142). Pleasant and unpleasant memories were differentiated by feelings, consequences, and level of unexpectedness. The most powerful discriminator of rape from other unpleasant memories was the degree to which they were less clear and vivid, contained a less meaningful order, were less well-remembered, and were less thought and talked about. Few "flashbulb" characteristics discriminated among memory types. Implications for clinical work with rape survivors were discussed.

Adolescent↗