The Banting Memorial Lecture 1973: Islet differentiation, organ culture, and transplantation.
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Adrenal Glands↗
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Results for “memory differentiation”
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TCR engagement regulates differential responsiveness of human memory T cells to Fas (CD95)-mediated apoptosis.
In this work, we have tried to establish whether human memory T cells may be protected from Fas (CD95)-induced apoptosis when correctly activated by Ag, and not protected when nonspecifically or incorrectly activated. In particular, we wanted to investigate the molecular mechanisms that regulate the fate of memory T cells following an antigenic challenge. To address this issue, we chose an experimental system that closely mimics physiological T cell activation such as human T cell lines and clones specific for viral peptides or alloantigens. We demonstrate that memory T cells acquire an activation-induced cell death (AICD)-resistant phenotype when TCRs are properly engaged by specific Ag bound to MHC molecules. Ag concentration and costimulation are critical parameters in regulating the protective effect. The analysis of the mechanisms involved in the block of CD95 signal transduction pathways revealed that the crucial events are the inhibition of CD95-associated IL-1beta-converting enzyme (ICE)-like protease (FLICE) activation and poly(ADP)-ribose polymerase cleavage, and the mRNA expression of FLICE-like inhibitory protein. Furthermore, we have observed that TCR-mediated neosynthesis of FLICE-like inhibitory protein mRNA is suppressed either by protein tyrosine kinase inhibitors or cyclosporin A. In conclusion, the present analysis of the effects of TCR triggering on the regulation of AICD suggests that AICD could be inhibited in human memory T cells activated in vivo by a foreign Ag, but may become operative when the Ag has been cleared.
Apoptosis↗
Differential sensitivity of IgG memory subpopulations to allogeneic thymocytes: positive and negative signals.
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Animals↗
Antigen-independent Th2 cell differentiation by stimulation of CD28: regulation via IL-4 gene expression and mitogen-activated protein kinase activation.
To delineate the molecular mechanisms regulating Th2 cell differentiation, CD28-mediated generation of Th2 effectors was analyzed. In the absence of TCR ligation CD28 stimulation induced Th2 differentiation of memory but not of naive CD4(+) T cells, whereas costimulation via CD28 and the TCR enhanced Th2 differentiation from naive T cells but suppressed it from memory T cells. Stimulation of T cells via the CD28 pathway, therefore, provided critical signals facilitating Th2 cell differentiation. By comparing the responses to CD28 stimulation in memory and naive T cells and by using specific inhibitors, signaling pathways were defined that contributed to Th2 differentiation. CD28-induced Th2 differentiation required IL-4 stimulation and the activation of the mitogen-activated protein kinases p38 and extracellular signal-regulated kinases 1/2. CD28 engagement directly initiated IL-4 gene transcription in memory T cells and induced activation of phosphatidylinositol 3-kinase, p38, and c-Jun NH(2)-terminal kinase/stress-activated protein kinase pathways. Extracellular signal-regulated kinase phosphorylation that was necessary for Th2 differentiation, however, required stimulation by IL-2. These results indicate that optimal TCR-independent generation of Th2 effectors requires coordinate signaling via the CD28 and IL-2 pathways. TCR-independent generation of Th2 effectors might provide a mechanism to control Th1-dominated cellular inflammation.
Adult↗
Making sense of inflammation, epigenetics, and memory CD8+ T-cell differentiation in the context of infection.
Recent findings suggest a new paradigm that early inflammatory cytokines promote the effector T-cell response while inhibiting the development of CD8+ T-cell memory. Although this opposing effect may appear paradoxical at first, it makes biological sense in the context of an infection, by ensuring a maximal effector response that will clear the pathogen. Once infection is controlled, the withdrawal of inflammatory cytokines allows the differentiation of effectors into long-lived memory cells that provide protective immunity against re-infection. Memory T cells differ from naïve T cells in their responsiveness to stimulation, which leads to the rapid expression of effector functions. The molecular basis for enhanced functionality of memory T cells remains largely unknown. Recent results indicate that certain epigenetic changes are imprinted in memory T cells that play an important role in keeping them poised to respond immediately upon antigen re-encounter. These epigenetic modifications occur as naïve T cells become activated and are influenced by factors that regulate memory formation. Thus, epigenetic changes are an integral component of memory T-cell differentiation, while inflammation plays an unexpected regulatory role in the process. These advances in our understanding of T-cell memory will undoubtedly help design unconventional vaccine strategies for inducing large populations of long-lived and functional memory CD8+ T cells.
CD8-Positive T-Lymphocytes↗
Screening for early dementia using memory complaints from patients and relatives.
This study examined whether the subjective impression of memory function might differentiate healthy elderly subjects from patients with memory complaints, and whether memory complaints differed between patients with and without a dementing illness. Both self-assessment and relatives' responses on a new memory questionnaire differentiated patient groups from control subjects. The relatives' form measuring deterioration in memory function over time identified dementing individuals from those with non-dementing causes for their memory complaints. Factor analysis indicated that patients' memory complaints correlated with depression rather than objective memory performance, while relatives' ratings correlated with objective memory scores, not depression. Stepwise discriminant function analyses showed that objective memory testing greatly improved specificity but not sensitivity of the subjective memory questionnaire alone.
Aged↗
A procedure for reducing errors in reports of life events.
Despite the widespread use of life event inventories, relatively little research has been conducted evaluating whether recall techniques can reduce reporting errors. This study evaluated whether memory aids would reduce errors in reports of life events and explored subjects' explanations for why they had given inconsistent answers to life event questions over the course of two interviews. Seventy-one college students were randomly assigned to two groups: memory aids (MA: n = 36) and no memory aids (NMA: n = 35). Memory aids, as used in this study, reduced errors in reports of life events as reflected in the following results: (1) significantly fewer subjects in the MA group reported dating events incorrectly; (2) subjects in the MA group consistently gave more reliable responses between the two interviews as measured by intraclass correlations; (3) there was a significantly higher test-retest reliability correlation for life events reported by MA subjects; and, (4) MA subjects recalled more life events and had fewer inconsistent responses. A further probe revealed that memory aids differentially aided recall of subjective as compared to objective life events. Overall, the findings of this study suggest that memory aid procedures can differentially reduce errors in reporting life events.
Adult↗
Memory B cells without somatic hypermutation are generated from Bcl6-deficient B cells.
After immunization with T cell-dependent antigens, the high-affinity B cells selected in germinal centers differentiate into memory B cells or long-lived antibody-forming cells. However, a role for germinal centers in development of these B lineage cells is still controversial. We show here that Bcl6-deficient B cells, which cannot develop germinal centers, differentiated into IgM and IgG1 memory B cells in the spleen but barely differentiated into long-lived IgG1 antibody-forming cells in the bone marrow. Mutation in the V-heavy gene was null in these memory B cells. Therefore, Bcl6 and germinal center formation are essential for somatic hypermutation, and generation of memory B cells can occur independently of germinal center formation, somatic hypermutation, and Ig class switching.
Adoptive Transfer↗
Memory function and the clinical differentiation of dementing disorder.
For the demented patient, relatively accurate bedside diagnosis is feasible by use of a carefully designed neurologic examination coupled with an understanding of the neuroanatomy of memory and related cognitive processes. Further confirmation of the clinical diagnosis by the application of selected laboratory diagnostic procedures can then result in an appropriate plan of treatment. With the promise of continued development of new therapeutic modalities for specific dementing illnesses such as Alzheimer's disease, a parallel improvement in diagnostic precision seems mandatory in order to permit detection of the disease at an earlier stage. A clinical anatomic approach with special emphasis on the understanding and assessment of memory function is suggested as a starting point. It is hoped that the serial examination of a significant number of patients by this method will eventually yield clues to aid in the earlier differential diagnosis of dementia.
Aged↗
IL-7 receptor expression levels do not identify CD8+ memory T lymphocyte precursors following peptide immunization.
Identification of the mechanisms underlying the survival of effector T cells and their differentiation into memory T lymphocytes are critically important to understanding memory development. Because cytokines regulate proliferation, differentiation, and survival of T lymphocytes, we hypothesized that cytokine signaling dictates the fate of effector T cells. To follow cytokine receptor expression during T cell responses, we transferred murine TCR transgenic T cells into naive recipients followed by immunization with peptide emulsified in adjuvant or pulsed on dendritic cells. Our findings did not correlate IL-7R alpha-chain and IL-2R beta-chain expression on effector CD8+ cells with the generation of memory T lymphocytes. However, we could correlate the extent of IL-7R alpha expression down-regulation on effector T cells with the level of inflammation generated by the immunization. Furthermore, our findings showed that the maintenance of a high level of IL-7R expression by effector T cells at the peak of the response does not preclude their death. This suggests that maintenance of IL-7R expression is not sufficient to prevent T cell contraction. Thus, our results indicate that expression of the IL-7R is not always a good marker for identifying precursors of memory T cells among effectors and that selective expression of the IL-7R by effector T cells should not be used to predict the success of vaccination.
Adoptive Transfer↗
Proliferation and differentiation potential of human CD8+ memory T-cell subsets in response to antigen or homeostatic cytokines.
Four human CD8+ T-cell subsets, naive (CCR7+CD45RA+), central memory (TCM, CCR7+CD45RA-), effector memory (TEM, CCR7-CD45RA-), and CD45RA+ effector memory cells (TEMRA, CCR7-CD45RA+) were compared for their capacity to proliferate and differentiate in response to antigen or homeostatic cytokines. Cytokine responsiveness and interleukin-15 receptor expression were low in naive T cells and progressively increased from TCM to TEM and TEMRA. In contrast, the capacity to accumulate in response to T-cell receptor (TCR) or cytokine stimulation showed a reciprocal pattern and was associated with resistance to cell death and Bcl-2 expression. Whereas all TCR-stimulated cells acquired a CD45RA-CCR7- phenotype, cytokine-stimulated cells maintained their phenotype with the exception of TCM cells, which expressed CCR7, CD45RA, and perforin in various combinations. Single CD8+ TCM cells, but not TEM cells, could be expanded with cytokines, and the obtained clones displayed several distinct phenotypes, suggesting that TCM cells are heterogeneous. Consistently, CCR4 expression in the CD8+ TCM pool discriminated CCR4+ type 2 polarized cells (Tc2) and CCR4-CTL precursors. Finally, ex vivo bromodeoxyuridine (BrdU) incorporation experiments revealed that memory subsets have different in vivo proliferation rates, with CCR4-TCM having the highest turnover and TEMRA the lowest. These results show that human CD8+ memory T-cell subsets have different proliferation and differentiation potentials in vitro and in vivo. Furthermore, they suggest that TEMRA cells are generated from a TCM subset upon homeostatic proliferation in the absence of antigen.
Antigen Presentation↗
Intermediate and long-term memories of associative learning are differentially affected by transcription versus translation blockers in Lymnaea.
Aerial respiratory behaviour in the pond snail, Lymnaea stagnalis, can be operantly conditioned. This associative learning then undergoes consolidation into a long-lasting memory which, depending on the training procedure used, causes intermediate-term memory (ITM; lasting 3 h) or long-term memory (LTM; lasting >6 h) to be formed. We determined the differential susceptibility of these two forms of memory to translation and transcription blockers. The injection of a translation blocker, Anisomycin, 2.5 h before training prevents the establishment of both ITM and LTM. On the other hand, injection of the transcription blocker Actinomycin D, 2.5 h before training, did not prevent the establishment of ITM, but did, however, prevent LTM formation. Thus in Lymnaea, following associative learning, both ITM and LTM are dependent on new protein synthesis. ITM appears to be dependent on protein synthesis from preexisting transcription factors, whilst LTM is dependent on protein synthesis from new transcription messages.
Animals↗
Cytokine control of memory T-cell development and survival.
Evidence has accumulated that cytokines have a fundamental role in the differentiation of memory T cells. Here, we follow the CD8+ T cell from initial activation to memory-cell generation, indicating the checkpoints at which cytokines determine the fate of the T cell. Members of the common cytokine-receptor gamma-chain (gammac)-cytokine family--in particular, interleukin-7 (IL-7) and IL-15--act at each stage of the immune response to promote proliferation and survival. In this manner, a stable and protective, long-lived memory CD8+ T-cell pool can be propagated and maintained.
Animals↗
Dendritic cells control B cell growth and differentiation.
We propose a model where human dendritic cell (DC) subsets control, in a coordinated fashion, B cell growth and differentiation. Plasmacytoid DCs drive memory B cell differentiation into effector plasma cell via type I interferon and IL-6. Type I interferon activates myeloid DCs that regulate B cell priming and acquisition of memory phenotype via IL-12, IL-6 and Blys/Baff. This model also integrates the role of antigen-specific T cells activated by myeloid DCs. Thus, protective humoral immunity results from a highly coordinated interplay of human DC subsets. This interplay may explain the spreading of immune response to deal with antigenic drift and to maintain an active immunity against mutating microbe. It may also provide an explanation for spreading of the autoimmune repertoire as autoimmunity develops.
Autoimmunity↗
Memory CD8 T-cell differentiation during viral infection.
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Acute Disease↗
Corpus striatum and traumatic brain injury.
The possibility of a 'subcortical' syndrome differentially affecting memory in traumatic brain injury (TBI) subjects was examined. Magnetic resonance imaging scans of 46 traumatic brain injured male patients were compared with those of 34 male control subjects. Surface area measurements of the corpus striatum were calculated for both groups. Results demonstrated no significant differences in corpus striatum surface area measurements. Additionally, TBI patients were grouped according to severity of injury, as well as degree of corpus striatum atrophy, and neuropsychological outcome was examined. There were modest (r = 0.35) but significant correlations between corpus striatum degeneration and the delayed recall trial and total score of the Rey Auditory Verbal Learning Test, but no other correlations between neuropsychological and corpus striatal surface area were significant. Because subcortical pathology may have a differential effect on memory, recognition and recall memory were further analysed, but no significant differences were found. TBI subjects with the smallest corpus striatum values did not test significantly different from TBI patients with normal corpus striatum values or differences in cortical atrophy, as determined by a ventricle-to-brain ratio. These findings suggest that there is not a unique pattern of subcortical pathology involving the corpus striatum in TBI.
Adolescent↗
Context, time, and memory retrieval in the interference paradigms of Pavlovian learning.
In this article I review research and theory on the "interference paradigms" in Pavlovian learning. In these situations (e.g., extinction, counterconditioning, and latent inhibition), a conditioned stimulus (CS) is associated with different unconditioned stimuli (USs) or outcomes in different phases of the experiment; retroactive interference, proactive interference, or both are often observed. In all of the paradigms, contextual stimuli influence performance, and when information is available, so does the passage of time. Memories of both phases are retained, and performance may depend on which is retrieved. Despite the similarity of the paradigms, conditioning theories tend to explain them with separate mechanisms. They also do not provide an adequate account of the context's role, fail to predict the effects of time, and overemphasize the role of learning or storage deficits. By accepting 4 propositions about animal memory (i.e., contextual stimuli guide retrieval, time is a context, different memories are differentially dependent on context, and interference occurs at performance output), a memory retrieval framework can provide an integrated account of context, time, and performance in the various paradigms.
Animals↗
Construction of an sIgE:FLAG-mIgE:GFP reporter mouse strain.
Like all other immunoglobulins, IgE can be secreted into the blood or expressed as a membrane receptor on the surface of B lymphocytes. Secreted immunoglobulins trace the antigen and contribute to its destruction. Membrane immunoglobulins accompany the B cell along its differentiation pathway, regulating processes like the induction and maintenance of immunological memory and differentiation of plasma cells. The regulation of the expression of IgE is very complex. A lot of positive and negative regulators influence the synthesis of IgE. In previous publications, we were able to show that the membrane IgE (mIgE) antigen receptor itself controls the quantity and quality of serum IgE produced. However, the knowledge about the regulatory function of the antigen receptor on these processes is at best limited. In the present paper, we present the construction of a reporter mouse strain, which will help us to follow an mIgE-bearing B cell during the immune response more precisely.
Animals↗