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Differential transcription directed by discrete gamma interferon promoter elements in naive and memory (effector) CD4 T cells and CD8 T cells.

Acquisition of the ability to produce gamma interferon (IFN-gamma) is a fundamental property of memory T cells and enables one subset (T helper 1 [TH1]) to deliver its effector functions. To examine regulation of IFN-gamma gene expression in a model system which recapitulates TH1 differentiation, we prepared reporter transgenic mice which express the luciferase gene under the control of proximal and distal regulatory elements (prox.IFN gamma and dist.IFN gamma) from the IFN-gamma promoter. Memory T cells, but not naive T cells, secreted IFN-gamma and expressed both prox.IFN gamma and dist.IFN gamma transcriptional activities. Naive T cells required priming to become producers of IFN-gamma and to direct transcription by these elements. While both CD4+ and CD8+ T cells produced IFN-gamma, only CD4+ T cells expressed prox.IFN gamma transcriptional activity. Induction of transcriptional activity was inhibited by known antagonists of effector T-cell populations. Cyclosporin A inhibited transcriptional activity directed by both elements in effector T cells. Elevated cyclic AMP inhibited transcriptional activity directed by prox.IFN gamma in primed CD4+ T cells but enhanced transcriptional activity directed by dist.IFN gamma in primed CD8+ T cells. Taken together, these data show that prox.IFN gamma and dist.IFN gamma transcriptional activities mirror IFN-gamma gene expression in naive and memory CD4+ T cells but suggest that differences exist in regulation of IFN-gamma gene expression in CD4+ and CD8+ T-cell subsets.

Animals↗

Differential effects of left and right anterior temporal lobectomy on verbal learning and memory performance.

The California Verbal Learning Test (CVLT) was utilized to identify the quantitative and qualitative alterations in verbal learning and memory performance that discriminated between patients following partial resection of the left (dominant) (n = 26) or right (nondominant) (n = 31) temporal lobe. Patients were administered the CVLT preoperatively and 6 months postoperatively, and the differential effects of laterality of resection on verbal learning and memory performance were determined. Following left temporal resection, patients showed significantly more serial clustering, a lower proportion of words recalled from the middle of the list, and more intrusion errors in free recall. Patients who underwent right temporal resection showed significantly greater recall of words from the middle and fewer words from the end of the list, more semantic clustering, and greater ability to recall verbal material after a short delay. These findings suggest that anterior temporal lobectomy (ATL) results in changes in the way verbal material is acquired, and affects the rate of forgetting. Patients who undergo left ATL become more dependent on less effective and efficient learning strategies, and forget the material that they have acquired at a faster rate. The opposite tendencies characterize patients who undergo right ATL.

Adult↗

Neurobehavioral functioning in children with fetal alcohol spectrum disorder.

Neurobehavioral functioning of 50 Canadian children diagnosed with Fetal Alcohol Spectrum Disorder (FASD) was evaluated. The aims of this study were to identify specific areas of weakness in neurobehavioral functioning, to examine whether neurobehavioral functioning was related to various predictor variables, and to determine which measures differentiated between children given a brain score of 2 (possible dysfunction) and 3 (probable dysfunction). Participants displayed difficulties with many aspects of intelligence, memory, executive functioning, and attention. Measures of Full scale and Verbal IQ, as well as memory for faces and numbers differentiated between children with a brain 2 and 3 ranking. An interesting pattern of strengths and weaknesses emerged as well as significant differences related to ethnic background, gender, and age. Aboriginal children and Caucasian children with FASD do not appear to show the same pattern of strengths and weaknesses in neurobehavioral functioning.

Adolescent↗

High-dose factor VIII inhibits factor VIII-specific memory B cells in hemophilia A with factor VIII inhibitors.

Hemophilia A in its severe form is a life-threatening hemorrhagic disease that is caused by mutations in the factor VIII (FVIII) gene (symbol F8). About 25% of patients who receive replacement therapy develop neutralizing antibodies that inhibit the function of substituted FVIII. Long-term application of high doses of FVIII has evolved as an effective therapy to eradicate the antibodies and to induce long-lasting immune tolerance. Little is known, however, about the immunologic mechanisms that cause the down-modulation of anti-FVIII antibodies by high doses of FVIII. We report that high doses of FVIII inhibit the restimulation of FVIII-specific memory B cells and their differentiation into antibody-secreting plasma cells in vitro and in vivo in a murine model of hemophilia A. The inhibition of memory B-cell responses is irreversible and not mediated by FVIII-specific T cells. Furthermore, it seems to involve the activation of caspases. We conclude that the inhibition of FVIII-specific memory B cells might be an early event in the down-modulation of anti-FVIII antibodies in patients with hemophilia A who receive high doses of FVIII.

Animals↗

Control of HL-60 myeloid differentiation. Evidence of uncoupled growth and differentiation control, S-phase specificity, and two-step regulation.

Myeloid differentiation of HL-60 human promyelocytic leukemia cells was studied during DMSO-induced differentiation. G 1/0-specific growth arrest could occur without the usual associated subsequent phenotypic differentiation into mature myeloid cells, suggesting that growth arrest and phenotypic differentiation are separately regulated. In the course of differentiating, the cells achieved a semi-stable intermediate state where they had a labile, pre-commitment memory of exposure to inducer, but were not yet committed to differentiation. This state was associated with a nuclear structural change previously found to be associated with the precommitment memory state. The process of differentiation could thus be resolved into two steps, early events up through development of pre-commitment memory and late events subsequents to pre-commitment memory. The kinetics of terminal cell differentiation indicated that the cellular regulatory event initiating a program of differentiation in response to inducer was S phase-specific. A comparison of the present results for DSMO to previous results for retinoic acid (RA)-induced HL-60 myeloid differentiation showed that the two inducers effect different cellular pathways for differentiation of HL-60 cells to mature myeloid cells, but with certain common features including the above S-phase specificity and pre-commitment memory.

Cell Cycle↗

Differential involvement of cortical muscarinic and NMDA receptors in short- and long-term taste aversion memory.

In conditioned taste aversion, an animal avoids a taste previously associated with toxic effects, and this aversive memory formation requires an intact insular cortex. In this paper, we investigated the possible differential involvement of cholinergic and glutamatergic receptors in the insular cortex in short-term memory (STM) and long-term memory (LTM) of taste aversion in rats. Taste aversion was induced by intraperitoneal administration of lithium chloride (a malaise-inducing drug) 15 min after experience with an unfamiliar taste. In order to test STM and LTM of taste aversion, taste stimulus was again presented 4 h and 72 h after lithium injection, respectively. During the acquisition, microinjection of the muscarinic antagonist, scopolamine, in the insular cortex before, but not after, the presentation of the new taste, abolished STM as well as LTM. Blockade of the NMDA receptor, in the insular cortex, by AP5 before, but not after, the presentation of the taste stimulus, impaired LTM but left STM intact. Moreover, when injected 1 h after malaise induction (i.e., during taste-illness association), AP5 disrupted both STM and LTM. These results suggest that activation of muscarinic receptors in the insular cortex is involved in the acquisition of taste memory, whereas NMDA receptors participate in taste memory consolidation. These data demonstrate that different neurochemical mechanisms subserve different memory phases. NMDA receptors are also probably involved in processing the visceral input, thus allowing subsequent taste-illness association. This indicates that in the same cortical area the same neurotransmitter system can be involved in distinct processes: taste memory consolidation vs. taste-illness association.

2-Amino-5-phosphonovalerate↗

Abnormal B cell differentiation in primary Sjögren's syndrome results in a depressed percentage of circulating memory B cells and elevated levels of soluble CD27 that correlate with Serum IgG concentration.

The percentage of CD27(+) B cells in peripheral blood (PB) of patients with primary Sjögren's syndrome (pSS) is significantly decreased compared to normals. In contrast, serum levels of the soluble form of CD27 (sCD27) are significantly higher in pSS patients, with a strong positive correlation between sCD27 and serum IgG levels. In vitro experiments demonstrate that normal B cells cultured under conditions driving plasma cell differentiation result in the production of substantial amounts of sCD27. Analyses of V(H)-region genes from sorted CD27(+) and CD27(-) B cells from pSS patients confirm that the CD27(+) population corresponds to the somatically mutated memory compartment, as in healthy individuals. Together our data indicate that in pSS, there is an abnormal differentiation of B cells to plasma cells resulting in a depression of the circulating memory B-cell pool and the release of significant amounts of sCD27 and IgG.

Adult↗

Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency.

No genetic defect is known to cause common variable immunodeficiency (CVID), a heterogeneous human disorder leading to adult-onset panhypogammaglobulinemia. In a search for CVID candidate proteins, we found four of 32 patients to lack ICOS, the "inducible costimulator" on activated T cells, due to an inherited homozygous deletion in the ICOS gene. T cells from these individuals were normal with regard to subset distribution, activation, cytokine production and proliferation. In contrast, naive, switched and memory B cells were reduced. The phenotype of human ICOS deficiency, which differs in key aspects from that of the ICOS-/- mouse, suggests a critical involvement of ICOS in T cell help for late B cell differentiation, class-switching and memory B cell generation.

Antigens, Differentiation, T-Lymphocyte↗

Effect of memory support and elicited production on fast mapping of new words by adolescents with Down syndrome.

PURPOSE: The purpose of this study was to determine whether memory support and elicited production differentially benefited fast mapping of new vocabulary (comprehension, production accuracy, and speed) in adolescents with Down syndrome (DS) compared with typically developing (TD) children matched for syntax comprehension. The study also examined predictors of individual difference within groups. METHOD: The ability of 19 adolescents with DS to fast map new noun vocabulary was compared with 18 TD children matched for syntax comprehension. The effects of memory support (5 examiner repetitions of the novel word vs. 1) and elicited production (2 repetitions by child vs. none) were evaluated in a repeated-measures design with counterbalancing of tasks. RESULTS: For novel word comprehension, low memory support impaired the TD but not DS participants. DS participants were slower to respond correctly in all conditions but benefited more from memory support than TD participants in speed of response. For novel word production, high memory support benefited all participants in the no-elicited-production condition. Elicited production improved performance equally in the 2 memory conditions. Standard comprehension measures predicted fast-mapped comprehension: vocabulary in the case of the DS group, syntax in the case of the TD group. Auditory short-term memory measures predicted fast-mapped production in the TD group but not the DS group. Hearing and grammatical morpheme comprehension predicted novel word production in the DS group. CONCLUSIONS: DS participants' speed of comprehension of fast-mapped words was differentially increased compared with the TD syntax-comprehension-matched group, by memory support. Elicited production improved production fast-mapping for all participants, and memory support improved it in the absence of elicited production. Comprehension predicted individual differences in fast-mapped comprehension in DS; in addition, hearing predicted production.

Adolescent↗

Impairments in working memory and decision-taking processes in monkeys in a model of Alzheimer's disease.

Studies were performed on two groups of animals (three monkeys in each). Monkeys of group I received unilateral intracerebroventricular injections of the neurotoxin p75-saporin (the ribosomal toxin saporin bound to monoclonal antibody to the p75NTR receptor), which elicits irreversible degradation of cholinergic neurons in the basal nuclei of Meynert, along with the enzyme dopamine-beta-hydroxylase (DBH-saporin), which impairs the functioning of noradrenergic neurons in the locus ceruleus. Monkeys of group II received injections of sterile physiological saline (0.9% NaCI). Monkeys were trained to discriminate stimuli containing different types of information (spatial frequency grids, geometric figures with different colors, different spatial relationships between objects) and perform spatial selection. The characteristics of working memory were identified in delayed differentiation tasks in monkeys of both groups before and after injections. These studies provided the first evidence that the development of Alzheimer's disease in rhesus macaques is characterized by a deficiency of working memory, this being based on impairment of two components of these processes. Impairment of the first in monkeys of group I was minifest in delayed visual differentiation as a significant decrease in correct responses. The extent of decreases depended on the duration of the delay and the type of visual information. Impairment of the second component, associated with decision-taking processes, was characterized by an increase in refusals to take decisions and was independent of the duration of delays and the type of visual information. Monkeys given injections of physiological saline showed no significant differences in these characteristics. The features of impairments in these memory components resulting from the development of Alzheimer's disease demonstrate that the structural-functional organization of cholinergic and noradrenergic mechanisms responsible for sensory processing differ from those involved in decision-taking.

Alzheimer Disease↗

Malonate promotes CD8+ T cell memory formation via protein malonylation.

Protein malonylation represents a recently identified posttranslational modification whose role in CD8+ T cell differentiation and functionality remains incompletely understood. In this study, we demonstrate that enhancing protein malonylation through sodium malonate (SM) treatment promotes CD8+ T cell memory formation in response to bacterial infection, subsequently potentiating recall responses. Comparative metabolomic analysis between SM-treated and control CD8+ T cells revealed significant metabolic alterations associated with protein malonylation. We present the first comprehensive proteomic analysis of lysine malonylation in murine CD8+ T cells, identifying 77 malonylation sites across 64 proteins involved in diverse cellular processes, particularly metabolic pathways. Malonylation of STAT6 was confirmed via the use of a specific chemical probe. Notably, we established that malonylation at the lysine 374 site of STAT6 results in increased TCF1 expression, due to alleviated transcriptional repression of TCF1 by STAT6. Collectively, our findings provide compelling evidence that protein malonylation plays a significant role in regulating CD8+ T cell memory formation.

Animals↗

Acute psychological stress alerts the adaptive immune response: stress-induced mobilization of effector T cells.

Influences of psychological stress on the acquired immune system have not consequently been investigated. We found acute psychological stress to cause an increase in CD56+ and CCR5+ effector T cells in the peripheral blood of healthy human subjects (N=22), while skin-homing CLA+ T cells decreased. At the same time, we observed a stress-induced decrease in CD45RA+/CCR7+ naive and CD45RA-/CCR7+ central memory T cells, while CD45RA-/CCR7- effector memory and CD45RA+/CCR7- terminally differentiated T cells increased. This T cell redistribution translated into an increase in T cells expressing perforin/granzyme B and in Epstein-Barr virus-specific, cytomegalovirus-specific and influenza virus-specific CD8+ T cells. Thus, acute stress seems to promote the retention of less mature T cells within lymphoid tissue or skin while effector-type T cells are mobilized into the blood in order to be able to rapidly migrate into peripheral tissues.

Acute Disease↗

Moods and memories: elation, depression, and the remembering of the events of one's life.

Three experiments investigated the influence of current mood states on the remembering of past events of one's own life. In the first and the second experiment, participants were induced to experience either the mood state of elation or the mood state of depression. They then reported events and experiences that had occurred during the previous week. In the first and the second experiments, using converging methods for assessing memory for past events, participants differentially reported past events and experiences whose affective quality was congruent with their current mood states: participants in elated mood states preferentially reported pleasant events and happy experiences, and participants in depressed mood states preferentially reported unpleasant events and unhappy experiences. Additional evidence from the second experiment suggests that the differential remembering of affectively positive or affectively negative events requires that, at the time of the remembering of these events, participants actually experience the mood states of elation or depression and not simply attempt to remember past events that could account for elation or depression. In the third experiment, designed to assess the plausibility of "experimental demand" interpretations of these findings, participants who experienced ostensibly effective mood inductions that were actually ineffective failed to manifest differential remembering of affectively positive and affectively negative events. Implications of this series of experiments for understanding the mechanisms that may link moods and memories, as well as the intrapersonal and the interpersonal consequences of mood states, are discussed.

Affect↗

The effects of neuraminidase and galactose oxidase on murine lymphocytes. I. Evidence for the differential delivery of signal(s) leading to cell proliferation and the differentiation of cytotoxic T cells.

The sequential treatment of normal C57BL/6 mouse spleen cell populations with neuraminidase (NA) and galactose oxidase (GO) resulted in cell proliferation, but not in the differentiation of cytotoxic T cells. In contrast, C57BL/6 spleen cells derived from animals primed 5 to 8 months earlier with alloantigen (P815 mastocytoma cells of the DBA/2 strain) both proliferated and demonstrated T cell-mediated cytotoxicity after NAGO stimulation. T cells differentiating into cytotoxic cells after NAGO treatment demonstrated properties similar to alloantigen-specific 'memory' T cells. These were: 1) cytotoxicity developed only from 'primed' cell populations, 2) cytotoxicity developed within 24 hr after NAGO treatment, 3) DNA synthesis was not required for the differentiation of cytotoxic cells during the first 24 hr of culture but both DNA synthesis and cell proliferation were required for the cytotoxicity developing after 24 hr, and 4) all cytotoxicity induced by NAGO showed specificity for the priming alloantigen. It was found, furthermore, that cytotoxicity could be induced at much lower GO concentrations than needed for increased DNA synthesis. We interpret this finding as an indication that NAGO can differentially deliver two 'signals' to T lymphocytes: one leading to cell proliferation, the other causing the differentiation of memory T cells into cytotoxic effectors.

Animals↗

Effector CD4 T cells are biochemically distinct from the memory subset: evidence for long-term persistence of effectors in vivo.

Memory T cell responses are believed to be mediated by long-lived memory T cells that arise directly from a subset of short-lived, activated effector T cells that have reverted to the resting state. Although widely accepted, definitive proof that memory T cells arise from effectors is lacking because of the inability to reliably distinguish these subsets based on known phenotypic or functional parameters. We have used a biochemical approach to distinguish effector and memory CD4 T cell subsets and follow the differentiative fate of effector cells in vivo. When examined biochemically, effector and memory CD4 T cells are strikingly distinct and exhibit qualitative and quantitative differences in tyrosine phosphorylation. These effector-specific patterns were identical in effectors derived either from naive CD4 T cells (primary effectors) or memory CD4 T cells (memory effectors). To monitor the fate of effector cells in vivo, Ag-activated CD4+ TCR-transgenic T cells were transferred into irradiated BALB/c mice. These TCR-transgenic CD4 T cells persisted in adoptive hosts for several months, gave a recall response to Ag, yet exhibited effector-specific biochemical profiles. These results suggest that a subset of effector CD4 T cells can persist in vivo and contribute to long-term immunity by mediating secondary immune responses.

Adoptive Transfer↗

Two subsets of memory T lymphocytes with distinct homing potentials and effector functions.

Naive T lymphocytes travel to T-cell areas of secondary lymphoid organs in search of antigen presented by dendritic cells. Once activated, they proliferate vigorously, generating effector cells that can migrate to B-cell areas or to inflamed tissues. A fraction of primed T lymphocytes persists as circulating memory cells that can confer protection and give, upon secondary challenge, a qualitatively different and quantitatively enhanced response. The nature of the cells that mediate the different facets of immunological memory remains unresolved. Here we show that expression of CCR7, a chemokine receptor that controls homing to secondary lymphoid organs, divides human memory T cells into two functionally distinct subsets. CCR7- memory cells express receptors for migration to inflamed tissues and display immediate effector function. In contrast, CCR7+ memory cells express lymph-node homing receptors and lack immediate effector function, but efficiently stimulate dendritic cells and differentiate into CCR7- effector cells upon secondary stimulation. The CCR7+ and CCR7- T cells, which we have named central memory (TCM) and effector memory (TEM), differentiate in a step-wise fashion from naive T cells, persist for years after immunization and allow a division of labour in the memory response.

Cells, Cultured↗