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Central memory and effector memory T cell subsets: function, generation, and maintenance.

The memory T cell pool functions as a dynamic repository of antigen-experienced T lymphocytes that accumulate over the lifetime of the individual. Recent studies indicate that memory T lymphocytes contain distinct populations of central memory (TCM) and effector memory (TEM) cells characterized by distinct homing capacity and effector function. This review addresses the heterogeneity of TCM and TEM, their differentiation stages, and the current models for their generation and maintenance in humans and mice.

Animals↗

The fuzzy frontier between subjective memory complaints and early dementia. A survey of patient management in German memory clinics.

BACKGROUND: Mild cognitive decline is frequent in the elderly population. Whether it is related to normal aging or an early phase of evolving dementia is difficult to ascertain with confidence, and accordingly there is a lack of consensus guidelines for diagnosis and therapy in such patients. We assessed the variability with which memory clinics deal with this problem in everyday practice. METHODS: We sent three fictitious case histories to all 85 German memory clinics that contained the results of clinical examination and neuropsychological test scores and asked for diagnosis and patient management. Patient 1 presented with complaints of mental decline but normal neuropsychological and neurological evaluation and normal daily living activities. Patient 2 came in as a control subject for a study and had impaired test scores but preserved daily living activities, and patient 3 was brought in by relatives with slight impairment of daily living activities and decline in some neuropsychological test scores but relatively spared memory scores. RESULTS: Most of the 51 respondents agreed in recommending further neuropsychological testing, a basic laboratory work-up, brain imaging, and a re-examination after 3-6 months. Yet, there was a high variability in the diagnostic terms used, in the additional diagnostic procedures proposed, and in the recommendations concerning therapeutic intervention and driving. CONCLUSIONS: The results reveal a need of practice guidelines for the use of diagnostic terms, therapeutic interventions and driving recommendations in patients between subjective memory complaints and early dementia.

Activities of Daily Living↗

Electrophysiological measures of episodic memory control and memory retrieval.

Event-related potentials (ERPs) index processes that occur before, during and after retrieval of information from episodic memory. In this selective review we provide a loose theoretical framework within which retrieval processes operating at these different stages can be considered. We go on to describe how ERPs have been employed in order to index processes operating at each of these stages. These data have contributed to current understanding of the processes that are engaged around the time of episodic memory retrieval, and also illustrate the potential that ERPs have for understanding in detail how memory retrieval processes changes in populations with memory impairments.

Electroencephalography↗

Long-lasting memory-resting and memory-effector CD4+ T cells in human X-linked agammaglobulinemia.

Conflicting results obtained from animal studies suggest that B cells play a role in maintaining long-term T-cell memory and in skewing T-cell response toward a T-helper 2 (T(H)2) phenotype. X-linked agammaglobulinemia (XLA) is a genetic human disease characterized by the lack of circulating B cells due to the mutation of Bruton tyrosine kinase. This disease thus represents a unique model for studying the role of B lymphocytes in regulating T-cell functions in humans. To this aim, we analyzed hepatitis B envelope antigen (HBenvAg)-specific T-cell memory in a series of XLA patients vaccinated against hepatitis B virus (HBV). We found HBenvAg-specific T lymphocytes producing interferon-gamma, interleukin-4, or both in the peripheral blood of XLA patients up to at least 24 months after completing the standard anti-HBV immunization protocol. The HBenvAg-specific T-cell frequencies and the percentage of patients with these responses were not significantly different from healthy vaccinated controls. By combining cell purification and enzyme-linked immunospot assay, we found that effector CD27- T cells, which promptly produced cytokines in response to antigen (Ag), and memory-resting CD27+ T cells, which required Ag restimulation to perform their functions, were maintained in both XLA patients and controls for up to 24 months after the last vaccination boost. These data strongly suggest that B cells are not an absolute requirement for the generation of effective T-cell memory in humans, nor do they seem to influence T(H)1/T(H)2 balance.

Adolescent↗

Differential susceptibility of naïve, central memory and effector memory T cells to dendritic cell-mediated HIV-1 transmission.

BACKGROUND: Dendritic cells (DC) have been proposed to facilitate sexual transmission of HIV-1 by capture of the virus in the mucosa and subsequent transmission to CD4+ T cells. Several T cell subsets can be identified in humans: naïve T cells (TN) that initiate an immune response to new antigens, and memory T cells that respond to previously encountered pathogens. The memory T cell pool comprises central memory (TCM) and effector memory cells (TEM), which are characterized by distinct homing and effector functions. The TEM cell subset, which can be further divided into effector Th1 and Th2 cells, has been shown to be the prime target for viral replication after HIV-1 infection, and is abundantly present in mucosal tissues. RESULTS: We determined the susceptibility of TN, TCM and TEM cells to DC-mediated HIV-1 transmission and found that co-receptor expression on the respective T cell subsets is a decisive factor for transmission. Accordingly, CCR5-using (R5) HIV-1 was most efficiently transmitted to TEM cells, and CXCR4-using (X4) HIV-1 was preferentially transmitted to TN cells. CONCLUSION: The highly efficient R5 transfer to TEM cells suggests that mucosal T cells are an important target for DC-mediated transmission. This may contribute to the initial burst of virus replication that is observed in these cells. TN cells, which are the prime target for DC-mediated X4 virus transmission in our study, are considered to inefficiently support HIV-1 replication. Our results thus indicate that DC may play a decisive role in the susceptibility of TN cells to X4 tropic HIV-1.

CD4-Positive T-Lymphocytes↗

Integrated memory for object, place, and context in rats: a possible model of episodic-like memory?

We report an investigation into memory for an object, its spatial location, and the context in which it appeared in rats. A novel task based on the spontaneous recognition paradigm is presented that requires memory for these three aspects. This task is performed easily by intact rats at delays of up to 1 hr. However, performance of the task is severely and selectively disrupted by transection of the fornix. Ability to perform this task is discussed in relation to models of episodic memory in animals, and we suggest that this task provides a simple and useful animal model of episodic memory for use with rats.

Animals↗

Working memory and reference memory in adult rats following limbic seizures induced at 21 or 90 days of age.

Rats were either seized or not seized at 21 days of age (weaning) or at 90 days of age with a single systemic injection of lithium (3 mEq/kg) and pilocarpine (30 mg/kg). When tested as adults (120 days of age) for spatial memory in the Olton radial maze, the rats that had been seized as adults exhibited about five times more working (short-term) memory errors than the other three groups which did not differ significantly from one another. The numbers of errors for long-term (reference) memory did not differ significantly among the four groups. The deficits in working memory for the group seized as weanlings and reported previously were not replicated. One possible explanation for this discrepancy might be differential effects upon brain organization associated with seizures evoked by injecting the pilocarpine 24 hr. rather than 4 hr. after the lithium.

Age Factors↗

Semantic context influences memory for verbs more than memory for nouns.

Three experiments revealed that memory for verbs is more dependent on semantic context than is memory for nouns. The participants in Experiment 1 were asked to remember either nouns or verbs from intransitive sentences. A recognition test included verbatim sentences, sentences with an old noun and a new verb, sentences with an old verb and a new noun, and entirely new sentences. Memory for verbs was significantly better when the verb was presented with the same noun at encoding and at retrieval. This contextual effect was much smaller for nouns. Experiments 2 and 3 replicated this effect and provided evidence that context effects reflect facilitation from bringing to mind the same meaning of a verb at encoding and at retrieval. Memory for verbs may be more dependent on semantic context because the meanings of verbs are more variable across semantic contexts than are the meanings of nouns.

Humans↗

The generation of Th memory in neonates versus adults: prolonged primary Th2 effector function and impaired development of Th1 memory effector function in murine neonates.

Immunization during the neonatal period often results in Th2-biased secondary responses. To understand the regulation of this phenomenon, we have examined all phases of Th development, from the generation of primary effectors to the duration of the primary effector stage to the production of memory effector function. First, we had previously reported that although primary responses in the neonatal lymph nodes are mature, mixed Th1/Th2-like, primary responses in the spleens of the same animals are exclusively Th2-like. To determine whether Th2-dominant secondary responses are due to the Th2-polarized primary function in the spleen, neonates were splenectomized before immunization. Even in the absence of primary neonatal splenic responses, the secondary responses of neonates were Th2 dominant. Thus, the overwhelmingly Th2 primary responses in the neonatal spleen are not required to generate Th2-dominant memory in the lymph nodes. Second, we have compared the kinetics of the primary response phase in neonates and adults. In adults, Ag-specific Th2 function disappeared rapidly from both the lymph nodes and spleen. In contrast, primary Th2 function persisted out to 5 wk in both neonatal organs. Third, the generation of Th memory responses was examined in animals initially immunized as neonates and in adults. These experiments demonstrated that neonates are selectively impaired in the development of Th1 memory effector function. Together, these results indicate that neonates are biased to Th2 function at all phases of an immune response.

Adjuvants, Immunologic↗

Role of MHC class II on memory B cells in post-germinal center B cell homeostasis and memory response.

We investigated the role of B cell Ag presentation in homeostasis of the memory B cell compartment in a mouse model where a conditional allele for the beta-chain of MHC class II (MHC-II) is deleted in the vast majority of all B cells by cd19 promoter-mediated expression of Cre recombinase (IA-B mice). Upon T cell-dependent immunization, a small number of MHC-II(+) B cells in IA-B mice dramatically expanded and restored normal albeit delayed levels of germinal center (GC) B cells with an affinity-enhancing somatic mutation to Ag. IA-B mice also established normal levels of MHC-II(+) memory B cells, which, however, subsequently lost MHC-II expression by ongoing deletion of the conditional iab allele without significant loss in their number. Furthermore, in vivo Ag restimulation of MHC-II(-) memory B cells of IA-B mice failed to cause differentiation into plasma cells (PCs), even in the presence of Ag-specific CD4(+) T cells. In addition, both numbers and Ag-specific affinity of long-lived PCs during the late post-GC phase, as well as post-GC serum affinity maturation, were significantly reduced in IA-B mice. These results support a notion that MHC-II-dependent T cell help during post-GC phase is not absolutely required for the maintenance of memory B cell frequency but is important for their differentiation into PCs and for the establishment of the long-lived PC compartment.

Animals↗

[External memory aids in prospective memory tasks].

This study investigated how the availability of external memory aids affects the cognitive processes in prospective memory tasks. Forty-eight subjects were instructed to memorize to-be-executed scripts and to-be-recalled scripts, and then perform the former scripts three minutes after the start of a recognition test. Before the recognition test, subjects in the timer and memo instruction conditions were informed they could utilize a timer and a memo, respectively. The results indicated that in the "no instruction" condition, recognition latencies were shorter for words from the to-be-executed scripts than for words from the to-be-recalled scripts (intention superiority effect). This did not occur in either the timer or memo instruction conditions. Moreover, the time-monitoring frequency was decreased only in the timer instruction condition. The results suggest that the external memory aids affect the rehearsal and monitoring processes in prospective memory tasks.

Adult↗

Sensorimotor memory for fingertip forces: evidence for a task-independent motor memory.

When repetitively lifting an object with randomly varying mechanical properties, the fingertip forces reflect the previous lift. We examined the specificity of this "sensorimotor memory" by observing the effects of an isolated pinch on the subsequent lift of a known object. In this case, the pinch force was unrelated to the fingertip forces necessary to grip the object efficiently. The peak grip force used to lift the test object (4 N weight) depended on the preceding task. Compared with repetitively lifting the 4 N test object, the peak grip force was 2 N greater when a lift of the same object was preceded by a lift in which a hidden mass was attached to the object to increase the weight to 8 N. This 2 N increase in grip force also occurred when subjects lifted the 4 N test object after pinching a force transducer with a force of 8 N. Thus, similar grip forces were stored in sensorimotor memory for both tasks, and reflected subjects' use of 7.9 +/- 1.1 N to lift the 8 N object. Similar effects occurred when the preceding pinch or lift was performed with the opposite hand. The peak lift force was unaffected by the isolated pinch, suggesting that a generalized increase in fingertip and limb forces did not occur. We conclude that the sensorimotor memory is not specific for lifting an object. It is doubtful that this particular memory stores the physical properties of objects or reflects a forward internal model for predictively controlling fingertip forces.

Acceleration↗

Episodic memory meets working memory in the frontal lobe: functional neuroimaging studies of encoding and retrieval.

Recent functional-neuroimaging studies have provided a wealth of new information suggesting that regions of the prefrontal cortex play a role in episodic memory encoding and retrieval. This review seeks to evaluate the results of these studies in the context of one general model that has proposed that the left prefrontal cortex is preferentially involved in episodic memory encoding, whereas the right prefrontal cortex is preferentially involved in episodic memory retrieval, irrespective of the type (e.g., modality) of information being remembered. The origins of this framework are considered in some detail and then all relevant functional-neuroimaging studies are critically reviewed. The results of this review fail to provide support for the functional-asymmetry model, suggesting instead that episodic memory encoding and retrieval may actually involve similar regions of the lateral prefrontal cortex when all factors relating to the type of stimulus material (i.e., modality), are appropriately controlled.

Brain Mapping↗

Making memories without trying: medial temporal lobe activity associated with incidental memory formation during recognition.

Structures in the medial portions of the human temporal lobes (MTL) play a vital role in the ability to learn new facts and events, whether such learning is intentional or incidental. We examined neural activity in the MTL both while participants studied pictures of novel scenes and while they attempted to recognize which scenes had been previously presented. In a second surprise test we assessed participants' memory for items that were presented only during the previous recognition memory test. We present a novel approach to cross-participant alignment of neuroimaging data that provides more precise localization and enhanced statistical power within regions such as the MTL. Using this technique, we observed that the amount of MTL activity predicted participants' ability to subsequently remember scenes not only during the intentional study task, but also during the first memory retrieval test when only incidental encoding occurred. This encoding-related activity during memory retrieval was in the same subregions of the MTL as encoding-related activity during intentional study and is hypothesized to be one of the primary reasons why retrieval-related activity is often difficult to observe with neuroimaging techniques.

Adolescent↗

The electrophysiological effects of a brain injury on auditory memory functioning. The QEEG correlates of impaired memory.

The effect of a brain injury on the quantitative EEG (QEEG) variables during an auditory memory activation condition was examined with 56 normal subjects and 85 mild traumatic brain-injured (MTBI) subjects. An analysis was conducted on the different response patterns of the two groups, the variables which were correlated with memory performance in the brain-injured group, and the variables which predicted the memory score for the combined two groups (normal and brain injured). The three conditions included the input task, the immediate recall, and the delayed recall task. The consistent effect of a brain injury was a lowering of the connectivity patterns in the beta1 and beta2 frequencies (phase and coherences) and increases predominantly in the relative power of beta1 (13-32Hz), which were correlated with the differences in recall. There is a subtle shift to right hemisphere/right temporal functioning and employment of the higher beta1 and beta2 frequencies (phase and coherence) in the response pattern of the MTBI subject. Memory functioning is predominantly positively correlated with connection activity (phase and coherence) and negatively correlated with beta activation at specific locations.

Adolescent↗

Quantitative measures of memory malingering on the Wechsler Memory Scale--Third edition in mild head injury litigants.

Wechsler Memory Scale-Third edition (WMS-III) performance in 25 mild traumatic brain injury (TBI) litigants who met the criteria for probable malingered neurocognitive dysfunction (MND) was compared with 50 nonmalingering subjects. The base rate for probable MND in the population studied was 27%. Overall, malingerers showed globally depressed memory function. They returned significantly poorer scores than nonmalingerers on all WMS-III indexes and subtests, and on selected WMS-III index difference scores and intelligence-memory difference scores. Using the minimum score returned in the nonmalingerers as the cut-off for malingering, the delayed auditory recognition memory tasks were highly effective in detecting malingering. Raw scores below 43 on the auditory recognition-delayed (AR-D) subtest or below 18 on word list II-recognition, identified around 80% of the malingerers. In a group of 50 severe TBI litigants, only a very small proportion (i.e., <10%) returned scores below the cut-offs for malingering for the mild TBI subjects.

Adolescent↗

Studies on B-cell memory. II. T-cell independent antigen can induce B-cell memory.

Both athymic nude mice and normal mice primed with a T-cell independent antigen, i.e. dinitrophenylated dextran (DNP-DE), at a sub-immunogenic dose, produced very poor anti-DNP responses to a later challenge with the same antigen. B-cell memory was expressed, however, as an enhanced IgM response after the challenge of the DNP-DE-primed mice with the T-cell dependent antigen (dinitrophenylated haemocyanin, DNP-KLH) in the presence of functional T-cells. Moreover, DNP-DE-primed spleen cells also revealed an enhanced IgM response after adoptive transfer into irradiated recipients and challenge with DNP-DE. The injections of DNP-DE-primed nude mouse serum into unprimed mice resulted in the reduction of anti-DNP response to the immunization with DNP-DE. These results indicate that (a) T-cell independent DNP-DE causes the differentiation of B cells not only into antibody-forming cells but also into memory cells, (b) these memory cells can be triggered in situ by the T-cell dependent DNP-KLH in the presence of helper T cells but not by T-cell independent antigen, and (c) some humoral factor(s) induced by DNP-DE-priming seems to interfere with the expression of B-cell memory only when challenged with T-cell independent DNP-DE.

Animals↗

Functionally dissociating aspects of event memory: the effects of combined perirhinal and postrhinal cortex lesions on object and place memory in the rat.

Reciprocal interactions between the hippocampus and the perirhinal and parahippocampal cortices form core components of a proposed temporal lobe memory system. For this reason, the involvement of the hippocampus in event memory is thought to depend on its connections with these cortical areas. Contrary to these predictions, we found that NMDA-induced lesions of the putative rat homologs of these cortical areas (perirhinal plus postrhinal cortices) did not impair performance on two allocentric spatial tasks highly sensitive to hippocampal dysfunction. Remarkably, for one of the tasks there was evidence of a facilitation of performance. The same cortical lesions did, however, disrupt spontaneous object recognition and object discrimination reversal learning but spared initial acquisition of the discrimination. This pattern of results reveals important dissociations between different aspects of memory within the temporal lobe. Furthermore, it shows that the perirhinal-postrhinal cortex is not a necessary route for spatial information reaching the hippocampus and that object familiarity-novelty detection depends on different neural substrates than do other aspects of event memory.

Animals↗