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PubMed2006

Control of CD4+ T-cell memory by cytokines and costimulators.

During T-cell priming, cytokines and costimulatory molecules provide important signals that determine the magnitude and quality of the response. Although the functions of defined cytokines and costimulators in the primary T-cell response are well characterized, much less is known about how these factors contribute to memory T-cell development and survival. Since memory cells are thought to be long-lived progeny of the primary response, it is conceivable that the same signals shaping initial T-cell expansion and differentiation also contribute to memory generation. Here, we review evidence and show novel data on the role of the cytokines interleukin-2 (IL-2) and IL-7 and the costimulator CD28 in CD4+ memory T-cell development. We emphasize that transient IL-2 and CD28 signals during priming imprint a long-lasting survival advantage in primed T cells, thus contributing to the persistence of a memory population. The requirement for IL-2 and CD28 signals is not linked to promoting T-cell division and expansion but most likely due to their capacity to (i) promote effector cell differentiation; (ii) induce survival proteins, and, as we discuss in more detail; (iii) program expression of receptors for 'memory survival factors' such as IL-7. Studies exploring the therapeutic potential of these insights are also discussed.

Animals↗
PubMed1998

Familiarity breeds differentiation: a subjective-likelihood approach to the effects of experience in recognition memory.

With repeated exposure, people become better at identifying presented items and better at rejecting items that have not been presented. This differentiation effect is captured in a model consisting of item detectors that learn estimates of conditional probabilities of item features. The model is used to account for a number of findings in the recognition memory literature, including (a) the basic differentiation effect (strength-mirror effect), (b) the fact that adding items to a list reduces recognition accuracy (list-length effect) but extra study of some items does not reduce recognition accuracy for other items (null list-strength effect), (c) nonlinear effects of strengthening items on false recognition of similar distractors, (d) a number of different kinds of mirror effects, (e) appropriate z-ROC curves, and (f) one type of deviation from optimality exhibited in recognition experiments.

Humans↗
PubMed2004

Towards a cellular definition of CD8+ T-cell memory: the role of CD4+ T-cell help in CD8+ T-cell responses.

Whereas the definition of B-cell memory is based on well-known cellular properties and differentiation steps, the process of T-cell memory generation was, until recently, less well understood. A series of recent reports, however, have drastically modified our notion of CD8(+) memory T cells. They show that, in addition to division, the generation of efficient memory cells requires a previously unknown differentiation process. As a whole, the generation of CD8(+) memory T cells appears to mimic the generation of memory B cells. Both processes depend on the help of CD4(+) T cells, they are irreversible, they have the same mechanism, and they occur progressively during the late expansion phase of the primary immune response.

Animals↗
PubMed2004

Differential effects of adrenergic and corticosteroid hormonal systems on human short- and long-term declarative memory for emotionally arousing material.

The effects of adrenergic and corticosteroid hormonal systems on emotional memory were measured in 64 young men. Placebo, propranolol (40 or 80 mg; beta blocker), or metyiapone (corticosteroid synthesis inhibitor) was administered before the viewing of a story composed of emotional and neutral segments. Short- and long-term declarative memory for the story was assessed. Propranolol 40 mg had no effects on declarative memory. Propranolol 80 mg impaired short- and long-term declarative memory for emotionally arousing material. Metyrapone did not impair short-term declarative memory but impaired long-term declarative memory for emotionally arousing and neutral material. Results demonstrate that adrenergic and corticosteroid hormonal systems differentially affect declarative memory for emotionally arousing and neutral material, and suggest that interactions between adrenal hormonal systems modulate emotionally arousing declarative memory in humans.

Adrenal Cortex Hormones↗
PubMed1995

The differential effect of alloantigen-blocking antibodies on unprimed and memory T helper cells.

Responsiveness to recall antigens by memory and naive T helper cells is different. To study whether such a difference is also applicable to affinity for allorecognition, we analyzed the effect of an IgG MLR blocking antibody separated from sera of patients with known kidney transplant chronic rejection on primed and unprimed CD4+ T cell alloreactivity. The results show that addition of the IgG fraction inhibits the patient's own unprimed T helper cell responses to a panel of four different alloantigens as well as a third-party mixed lymphocyte response. The same IgG fraction inhibited third-party naive T helper cell, but not autologous unprimed T helper cell, proliferation to adherent anti-CD3 antibody, which suggests that the mechanism of inhibitory action of the IgG is allogeneic-dependent. This IgG also did not induce inhibition of any of the T helper cell clone responsiveness, raised from the same or other patients, when stimulated with the same alloantigens used for unprimed cell alloactivation. Differential responses of naive and memory CD4+ T cells to alloantigens may explain some differences between the in vivo and in vitro systems and why allograft rejection can proceed in the presence of allogeneic blocking antibodies.

Base Sequence↗
PubMed2004

Expression of CCR7 in multiple sclerosis: implications for CNS immunity.

It is unclear how immune cells traffic between the lymphoid compartment and the central nervous system (CNS), which lacks lymphatic vessels and is shielded by the blood-brain barrier. We studied the expression of CCR7, a chemokine receptor required for migration of T cells and dendritic cells (DCs) to lymphoid organs, in the CNS of patients with multiple sclerosis (MS) to gain insight into pathways for CNS immune cell trafficking. Inflamed MS lesions contained numerous CCR7+ myeloid cells expressing major histocompatibility complex class II, CD68 and CD86, consistent with maturing DCs. CCR7+ DCs also were identified in cerebrospinal fluid (CSF). These observations suggested that the afferent limb of CNS immunity is comprised, in part, of DCs, which are generated within the CNS and migrate to deep cervical lymph nodes through the CSF after antigen capture. Ninety percent of CSF T cells expressed CCR7 and CSF from patients with MS was relatively depleted of CCR7-negative effector-memory T cells. In contrast, all T cells in parenchymal MS lesions lacked CCR7, indicating local retention and differentiation of central-memory T cells upon restimulation by antigen within the CNS. These data suggested that the efferent limb of CNS immunity is executed by central-memory T cells, which enter CSF directly from the circulation.

Adolescent↗
PubMed2006

Exogenous cortisol shifts a motivated bias from fear to anger in spatial working memory for facial expressions.

Studies assessing processing of facial expressions have established that cortisol levels, emotional traits, and affective disorders predict selective responding to these motivationally relevant stimuli in expression specific manners. For instance, increased attentional processing of fearful faces (attentional bias for fearful faces) is associated with fear and anxiety and diminishes after administration of the anxiolytic hormone testosterone. Conversely, attentional bias for angry faces has been associated with higher levels of approach motivation (e.g. anger) and testosterone, but lower levels of cortisol. This negative relation between cortisol levels and bias for angry faces was also seen in a test of biased working memory performance. However, previous research suggests that exogenous glucocorticoids acutely decrease fearful and inhibited behavior and increase aggressiveness. Hypothesizing from these findings, the present study tested this spatial working memory for faces of various emotional expressions (neutral, happy, fearful, and angry) after double-blind, placebo-controlled administration of 40 mg cortisol in 18 healthy young men. It was predicted that cortisol would acutely attenuate memory bias for fearful expressions while increasing memory bias for angry expressions, in effect creating a shift in biased motivated memory from fear to anger. Results largely confirmed the hypotheses. This is the first causal evidence that cortisol differentially regulates spatial working memory for different facial expressions. Possible biological mechanisms are discussed.

Adolescent↗
PubMed2005

[Memory and planning].

The years before and after retirement are characterized by substantial changes in the lifes' of aging individuals. However, the same changes may be appraised as stressful, neutral, or positive, depending on the available skills, experiences, and future expectations. In other words, the subjective experience of cognitive aging strongly determines health-related behaviors and, thus, the effectiveness of treatments. An area of increasing concern in this age group is the development of one's cognitive abilities. The demand for adequate trainings to preventively maintain cognitive skills plays an important role. Persons may also start worrying if observed changes in their memory performance are still in the range of normal functioning or if they may represent early indications of dementia. This paper (a) briefly describes normal cognitive development between 50 and 75 years, (b) provides examples for the plasticity of cognitive abilities, (c) highlights the importance of subjective memory complaints for the detection of mental health and memory problems, and (d) suggests a procedure to help detecting memory problems early on.

Aged↗
PubMed1990

Psychological factors in irritable bowel syndrome.

This paper describes the prevalence and incidence of psychiatric disorders in IBS patients using a standardized psychiatric interview, and proposes a psychological model for investigating one aspect of IBS. Forty-four IBS patients and 28 nonclinical participants received a psychiatric interview (Diagnostic Interview Schedule) and completed the Lie Scale of the Eysenck Personality Inventory (L-EPI). Results indicated that a significant percentage (59%) of the IBS group met DSM-III criteria for a psychiatric disorder within the last year, far more than occurred in the matched nonclinical comparison group. Relative to the comparison group, the IBS group also had significantly higher lie scores on the EPI indicating a response style of social desirability. On the basis of these findings, together with earlier work by Latimer's group, a conceptual model was formulated on the notion that some IBS patients may have a self-schema (i.e. knowledge of self, stored in memory) characterized by social desirability. We suggest that the construct of self-schema may be helpful in differentiating IBS from psychiatric groups both conceptually and therapeutically.

Adult↗
PubMed2001

fMRI measurement of brain dysfunction in alcohol-dependent young women.

BACKGROUND: Studies of brain functioning in alcohol-dependent adults have produced varied results but generally suggest that alcohol affects brain functioning and that relatively short durations of heavy drinking may adversely affect women. It remains unclear when in the course of alcohol dependency and at which developmental stage these brain changes emerge. Our neuropsychological studies have indicated that drinking-related neurocognitive effects occur as early as adolescence (Brown et al., 2000; Tapert & Brown, 1999). This study seeks to characterize brain regions that subserve the affected neurocognitive functions. METHODS: Alcohol-dependent young women (n = 10) were recruited from a longitudinal study of alcohol- and drug-abusing youth, all of whom met criteria for alcohol dependence. Control participants (n = 10) had no history of alcohol or drug problems and were comparable with alcohol-dependent participants on age (18-25 years), family history of alcohol use disorders, and education. After a minimum of 72 hr of abstinence, functional magnetic resonance imaging, neuropsychological, alcohol/drug involvement, and mood data were collected. Participants performed spatial working memory and vigilance tasks during functional magnetic resonance imaging acquisition to probe brain response. RESULTS: Alcohol-dependent women demonstrated significantly less blood oxygen level-dependent response than controls during the spatial working memory task in the right superior and inferior parietal, right middle frontal, right postcentral, and left superior frontal cortex, after controlling for the baseline vigilance response. CONCLUSIONS: Working memory produces a larger neuronal response in some cortical regions than vigilance. Alcohol-dependent women showed less differential response to working memory than controls in frontal and parietal regions, especially in the right hemisphere. Heavy, chronic drinking appears to produce adverse neural effects that are detectable by functional magnetic resonance imaging.

Adolescent↗
PubMed2003

Verbal learning in Alzheimer's dementia.

Many recent findings in Western countries suggest that episodic recall is the most sensitive discriminator between patients with mild Alzheimer disease (AD) and the normal elderly, while semantic memory tends best to differentiate between moderate and severe AD patients. The present study is the first to examine in detail the episodic memory of Chinese AD patients in Hong Kong with a locally developed list learning test, comparing procedures that do or do not encourage the use of semantic organization. The performance of 28 AD patients was compared to that of 30 normal controls. AD patients did significantly worse in terms of acquisition and retention and also benefited significantly less from external organization cues. In the discriminant function analysis, the rate of forgetting in the random condition and the total retention score in the blocked condition were found to be the best predictors for differentiating between AD patients and controls. On the other hand, in the differentiation between mild and moderate AD, semantic clustering in the blocked condition was found to be the best predictor. Results of the present study were discussed in the light of the previous findings reported in the Western countries and the neuropathological changes of AD patients.

Aged↗
PubMed2004

Antigen-independent memory CD8 T cells do not develop during chronic viral infection.

Memory T cells can persist for extended periods in the absence of antigen, and long-term T cell immunity is often seen after acute infections. Paradoxically, there have been observations suggesting that T cell memory may be antigen-dependent during chronic infections. To elucidate the underlying mechanisms we have compared memory CD8 T cell differentiation during an acute versus chronic infection by using the mouse model of infection with lymphocytic choriomeningitis virus. We found that during a chronic infection virus-specific CD8 T cells failed to acquire the cardinal memory T cell property of long-term antigen-independent persistence. These chronically stimulated CD8 T cells were unable to undergo homeostatic proliferation, responded poorly to IL-7 and IL-15, and expressed reduced levels of the IL-7 and IL-15 receptors, thus providing a possible mechanism for the inability of these cells to persist long term in the absence of antigen. In striking contrast, virus-specific memory CD8 T cells that developed after an acute lymphocytic choriomeningitis virus infection could persist without antigen, were capable of self-renewal because of homeostatic proliferation, responded efficiently to IL-7 and IL-15, and expressed high levels of receptors for these two cytokines. Thus, memory CD8 T cells generated after acute infections are likely to have a competitive advantage over CD8 T cells that develop during chronic infections. These findings raise concerns about using vaccines that may persist and also suggest that there may be limitations and challenges in designing effective immunological interventions for the treatment of chronic infections and tumors.

Adoptive Transfer↗
PubMed2004

Differential regulation of P-selectin ligand expression in naive versus memory CD4+ T cells: evidence for epigenetic regulation of involved glycosyltransferase genes.

Lymphocytes are targeted to inflamed sites by specific "homing" and chemokine receptors. Most of them, including ligands for P- and E-selectin, are absent from naive CD4(+) T cells and become induced after activation and differentiation in effector/memory cells. Polarized effector cells are characterized by the rapid production of distinct cytokines upon restimulation. Their cytokine memory is in part controlled by epigenetic imprinting during differentiation. Here we ask whether a similar mechanism could regulate selectin ligand expression, mediating entry into inflamed sites, notably within the skin. We report that acquisition of selectin ligands by naive but not memory CD4(+) cells depends on progression through the G(1)/S phase of the cell cycle-a phase susceptible to modification of the chromatin structure. Cell-cycle arrest prevented transcriptional activation of glycosyltransferases involved in the generation of selectin ligands, suggesting that progression through the cell cycle is required to unlock their genes. Artificial DNA demethylation strongly increased the frequency of selectin ligand-expressing cells, suggesting that DNA methylation keeps transferase genes inaccessible in naive T cells. Due to these findings we propose that selectin-dependent inflammation-seeking properties are imprinted by epigenetic modifications upon T-cell differentiation into effector cells.

Animals↗
PubMed2003

Measuring duration mismatch negativity.

OBJECTIVE: Automatic comparisons of sound duration in auditory sensory memory are typically investigated by comparing event-related potentials (ERPs) to standard and deviant stimuli presented in oddball blocks. Deviants elicit mismatch negativity (MMN). This procedure might overestimate an MMN contribution reflecting automatic sensory memory processes because of differential states of refractoriness of respectively recruited neural populations [Neuroreport 1996;7:3005; Psychophysiology 2001;38:723]. Here, memory-comparison-based Duration MMN contributions were investigated using various experimental protocols. METHODS: Memory-comparison-based first-order Duration MMN was investigated using 4 blocked conditions: (a) descending Deviant (100 ms, P=0.14), 150 ms Standard; (b) reverse ascending Deviant (150 ms), 100 ms Standard; (c) Control comprised of 7 equiprobable durations between 25 and 175 ms; and additionally (d) equiprobable tones between 100 and 400 ms. Using the former 3 conditions, Deviants, Standards and Controls were physically identical. RESULTS: Comparing Deviants and Controls excluded potential refractoriness effects, and a decomposition of memory-comparison-based MMN and residual MMN was demonstrated. Genuine Duration MMN was also obtained in the deviant-standard-reverse comparison. CONCLUSIONS: Using a blocked control condition yielded equivalent results to reversing the role of deviant and standard in two separate oddball blocks. Using the reverse ascending deviant condition is thus sufficient as a control.

Acoustic Stimulation↗
PubMed2006

CD127+CCR5+CD38+++ CD4+ Th1 effector cells are an early component of the primary immune response to vaccinia virus and precede development of interleukin-2+ memory CD4+ T cells.

The stages of development of human antigen-specific CD4+ T cells responding to viral infection and their differentiation into long-term memory cells are not well understood. The inoculation of healthy adults with vaccinia virus presents an opportunity to study these events intensively. Between days 11 and 14 postinoculation, there was a peak of proliferating CCR5+CD38+++ CD4+ effector cells which contained the cytotoxic granule marker T-cell intracellular antigen 1 and included gamma interferon (IFN-gamma)-producing vaccinia virus-specific CD4+ T cells. The majority of these initial vaccinia virus-specific CD4+ T cells were CD127+ and produced interleukin-2 (IL-2) but not CTLA-4 in response to restimulation in vitro. Between days 14 and 21, there was a switch from IFN-gamma and IL-2 coexpression to IL-2 production only, coinciding with a resting phenotype and an increased in vitro proliferation response. The early CCR5+CD38+++ vaccinia virus-specific CD4+ T cells were similar to our previous observations of human immunodeficiency virus (HIV)-specific CD4+ T cells in primary HIV type 1 (HIV-1) infection, but the vaccinia virus-specific cells expressed much more CD127 and IL-2 than we previously found in their HIV-specific counterparts. The current study provides important information on the differentiation of IL-2+ vaccinia virus-specific memory cells, allowing further study of antiviral effector CD4+ T cells in healthy adults and their dysfunction in HIV-1 infection.

ADP-ribosyl Cyclase 1↗
PubMed2002

Cytokines and their role in lymphoid development, differentiation and homeostasis.

PURPOSE OF REVIEW: The development of lymphoid tissues as well as the ultimate differentiation of naïve and memory T cells are dependent on cytokines. In this review, we will focus on recent advances in the understanding of molecular mechanisms that regulate lymphoid development, homeostasis and tolerance. RECENT FINDINGS: Cytokines play a critical role in the development and differentiation of lymphoid cells. In addition, newer data indicate important roles of interleukin-7 and interleukin-15 in lymphoid homeostasis and memory. Furthermore, a new family of heterodimeric cytokines comprising interleukin-12, interleukin-23 and -27 is important for differentiation of helper T cells and cell-mediated immunity. Finally the importance of tumor necrosis factor superfamily members in the development of lymphoid organs has recently been elucidated and will be discussed in detail. SUMMARY: New cytokines and receptors continue to be identified. The discovery and characterization of cytokines, their receptors and signaling molecules will provide a more complete understanding of normal lymphoid development, differentiation and function. In addition, this knowledge should improve our understanding of the pathogenesis of immunological diseases and hopefully will provide new treatment strategies.

Cytokines↗