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PubMed1990

T cells in inductive and effector compartments of the intestinal mucosal immune system of nonhuman primates differ in lymphokine mRNA expression, lymphokine utilization, and regulatory function.

To define further the basis of T cell function in the inductive and effector limbs of the normal intestinal immune system, the capacity of mucosal lymphocytes to produce and use lymphokines and their effects on regulation of Ig production were determined in normal nonhuman primates. Northern blots of RNA from mitogen-activated lamina propria T cells contained more mRNA for IL-2 and IFN-gamma than did mesenteric lymph node T cells. In comparison with lymphocytes from peripheral sites, there was high expression of IL-4 and IL-5 mRNA in both mesenteric lymph node and lamina propria T cells. In studies of lymphokine utilization, T cells from lamina propria had high IL-2-induced but no IL-4-induced proliferative responses. In contrast, mesenteric lymph node T cells had high IL-4-induced and lower IL-2-induced proliferative responses compared with lamina propria T cells. Lamina propria T cells had higher helper activity in PWM-stimulated cultures and exhibited less inhibition by IL-4 than did mesenteric lymph node T cells. These data and previous studies suggest that T cells in an inductive site such as the mesenteric lymph node are a mixed population containing both "naive" cells with low potential for IFN-gamma and IL-2 production and differentiated cells with high potential for IL-4 and IL-5 production. In contrast, the data suggest that T cells in the effector compartment of the lamina propria are comprised primarily of differentiated "memory" cells that produce high levels of IL-2, IFN-gamma, IL-4, and IL-5, have high helper activity, and have a more limited ability to proliferate in response to lymphokines such as IL-4.

Animals↗

PubMed1979

Thymus dependence of the IgG response: role of T cells is restricted to non-specific rather than antigen-specific factors.

We have been studying the requirement for T cells in the proliferation and maturation of partially differentiated memory cells into IgG antibody secreting cells. The role of T cells in such a system can be replaced by non-antigen-specific T-cell factor(s) present in the supernatant of a 24 h mixed lymphocyte reaction (TRF) but not by antigen-specific factors released upon in vitro induction of T-helper cells with antigen. A combination of antigen-specific and non-specific factors showed no evidence of synergy between the two sets of factors and we therefore conclude that the antigen-specific factors tested play no role in the later stages of B-memory cell maturation to IgG-antibody secreting cells.

Animals↗

PubMed1996

The differentiation of human memory B cells into specific antibody-secreting cells is CD40 independent.

It is generally accepted that memory B cells can be defined by their ability to produce, upon antigenic challenge, somatically mutated antibody molecules characterized by an increased affinity and by the expression of a downstream heavy chain isotype. However, the inability to isolate this particular B cell compartment has precluded the study of memory B lymphocyte physiology in man. We previously reported on the identification of an IgD- B cell subset in human tonsils that we defined as CD38- B cells, whose phenotype is highly reminiscent of that of memory B lymphocytes from the splenic marginal zone of rodents. In the present study, we developed a model of the measles virus (MV)-specific secondary antibody response in vitro to assess the presence of memory B lymphocytes in different B cell subsets isolated from human tonsils and explore the activation requirements of human memory B cells. Our findings show that the memory B cell pool resides in the CD38- B cell subpopulation and that the differentiation of MV-activated memory B cells into antibody-secreting cells can be achieved upon co-stimulation with interleukin (IL)-2 and IL-10, but does not require engagement of CD40. Interestingly, the CD40-mediated signal was found to synergize with Ig-cross-linking agents for the proliferation of memory B cells, but strongly suppressed their capacity to differentiate along the plasmacytoid pathway. Collectively, our results suggest that the CD40 signaling pathway is instrumental for the clonal expansion of the memory B cell pool, but does not operate in the later phase of the response, which allows their maturation into antibody-secreting cells.

Antibodies, Viral↗

PubMed2007

Negative differential resistance and memory effect in diodes based on 1,4-dibenzyl C60 and zinc phthalocyanine doped polystyrene hybrid material.

Negative differential resistance (NDR) and memory effect were observed in diodes based on 1,4-dibenzyl C60 (DBC) and zinc phthalocyanine doped polystyrene hybrid material. Certain negative starting sweeping voltages led to a reproducible NDR, making the hybrid material a promising candidate in memory devices. It was found that the introduction of DBC enhanced the ON/OFF current ratio and significantly improved the memory stability. The ON/OFF current ratio was up to 2 orders of magnitude. The write-read-erase-reread cycles were more than 106, and the retention time reached 10,000 s without current degradation.

Journal Article↗

PubMed2005

STAT5 regulates the self-renewal capacity and differentiation of human memory B cells and controls Bcl-6 expression.

It is unknown how B cells that mature during a germinal center reaction 'decide' between plasma or memory cell fate. Here we describe a previously unknown subpopulation of B cells in the human germinal center that is characterized by tyrosine phosphorylated transcriptional activator STAT5. These cells had an activated centrocyte phenotype and had abundant expression of BCL6 but low expression of PRDM1, both encoding transcriptional repression proteins. Using RNA interference and ectopic expression of constitutively activated forms of STAT5, we demonstrate here a function for STAT5 in the self-renewal of B cells in vitro. STAT5b isoform seemed to directly upregulate Bcl-6, and ectopic expression of Bcl-6 in B cells resulted in self-renewal and inhibition of plasma cell differentiation. These data indicate that activation of STAT5 is involved in regulation of memory B cell differentiation.

B-Lymphocytes↗

PubMed2002

Repertoire of antibody response in bone marrow and the memory response are differentially affected in aging mice.

The primary burst of Ab and germinal center (GC) formation in response to T-dependent Ag is compromised in aging mice. Here we examine the effects of aging on the post-GC phase of memory B cell differentiation and the late Ab repertoire maturation in bone marrow (BM) in mice immunized with a hapten nitrophenyl coupled to chicken gamma-globulin. Specific Ab-forming cells (AFC) with mutated V(H) genes accumulated preferentially in the BM of aged mice, although the AFC numbers and average number of mutations per V(H) were lower, and the D gene usage was less restricted compared with those in the young animals. However, the repertoire of AFC after an Ag boost demonstrated the hallmarks of Ag selection, including the recurrent mutations and canonical VD rearrangements, similar to the late primary response in young animals. It is postulated that the Ab repertoire maturation in aged mice is delayed and may be notably improved by repeated immunizations.

Aging↗

PubMed2006

Differential patterns of memory performance in relapsing, remitting and secondary progressive multiple sclerosis.

BACKGROUND: Memory dysfunction is common in multiple sclerosis (MS). A retrieval failure has been reported as the primary cause for the memory deficits, although some studies also described a faulty acquisition. AIMS: The aim of the study was to examine memory function in relapsing remitting (RR) and secondary progressive (SP) MS patients, analyze the patterns of performance and to investigate whether disease course influences this performance. DESIGN AND SETTINGS: Case-control prospective study conducted in a clinical setting. MATERIALS AND METHODS: Fifty-five RR, 23 SP MS patients and 80 normal subjects were evaluated with a comprehensive neuropsychological battery. Memory was assessed with tasks from the Signoret memory battery. Attention and executive function were also assessed. STATISTICAL ANALYSIS: Univariate analysis of variance, Mann-Whitney U-test, multivariate logistic regression and Chi-square test were used as appropriate. RESULTS: MS patients performed significantly worse than controls on almost all measures of memory (P < 0,001). MS subgroups differed in tasks of delayed recall (logical memory- P =0,019; wordlist delayed recall, P < 0,001), semantic cued recall (P < 0,001), recognition trials (P =0,006) rate of forgetting (P < 0,001) and confabulation and intrusion errors (P =0,004). CONCLUSIONS: Memory is consistently impaired in MS patients and disease course differentially affects the pattern of performance. SP patients show greater difficulties and a more pervasive pattern of dysfunction than RR patients. Delayed recall was the most affected memory measure and performance on this task discriminates between RR and SP MS patients. Relapsing remitting patients performed within the mildly impaired range while SP patients showed a moderate to severe impairment.

Adult↗

PubMed2001

Differential episodic and semantic memory performance in Alzheimer's disease and vascular dementias.

Differential performance on measures of episodic and semantic memory were examined in AD, cortical vascular dementia (CVaD), subcortica] vascular dementia (SVaD), and controls. Groups were matched on age, education, and gender; dementia groups also were matched on severity. Recognition/retrieval differences were found only between SVaD and AD groups, not between CVaD and AD. Thus, recognition/retrieval differences are likely secondary to subcortical pathology rather than to vascular etiology per se. Similarly, significant numbers of memory errors were associated with cortical pathology, regardless of etiology. Error rate differences were found only between SVaD and AD groups, not between CVaD and AD. Finally, rapid forgetting was unique to AD; however, since no difference was found between SVaD and AD, rapid forgetting may occur only as AD progresses. No semantic memory measure differentiated AD from either CVaD or SVaD subjects. Results suggest that some previously reported episodic differences may be due to cortical versus white matter subcortical pathology, rather than to AD versus vascular etiology.

Aged↗

PubMed1999

Differential genetic influence for components of memory in aging adult twins.

OBJECTIVE: To investigate the relative proportion of genetic and environmental contributions to verbal memory in community-dwelling World War II veteran twins. DESIGN: The California Verbal Learning Test (CVLT) was administered to 94 monozygotic (MZ) and 89 dizygotic (DZ) elderly male twin pair participants in the fourth examination of the National Heart, Lung, and Blood Institute Twin Study. SETTING: Subjects voluntarily participated on an outpatient basis at a research or medical center facility in 1 of 4 sites in the United States. PARTICIPANTS: Subjects had a mean age of 71.8 years (SD, 2.9 years), a mean educational level of 13.6 years (SD, 2.8 years), and no history of stroke and/or a Mini-Mental State Examination score of 23 or greater. MAIN OUTCOME MEASURES: Twin pair similarity in performance on 4 factor analytically derived components of the CVLT measuring verbal learning and memory, response discrimination, learning strategy, and recognition memory. RESULTS: The MZ intraclass correlation was significantly larger than the DZ correlation for verbal learning and memory (I<.001) but not for the other 3 components of memory. Using maximum likelihood methods, the best-fitting genetic model indicated that verbal learning and memory has a substantial genetic component (56% of total variance), whereas response discrimination has a much smaller, although still detectable, genetic component (24% of total variance). There is no evidence of genetic influence on learning strategy or recognition memory. CONCLUSION: Differential contribution of genetic and environmental influences to specific components of memory suggest that, in this group of elderly male twin pairs, some components may be more amenable to intervention than others.

Aged↗

PubMed2006

Costimulation of naive human CD4 T cells through intercellular adhesion molecule-1 promotes differentiation to a memory phenotype that is not strictly the result of multiple rounds of cell division.

The process by which naive T cells become activated, differentiate into effector cells and ultimately generate long-lived memory cells is dependent upon a number of factors, including the costimulatory signals received by the T cell. To best understand the multiple events involved, it is important to understand the potential contributions by individual signalling proteins using both in vitro and in vivo studies. Here, the potential for costimulation through intercellular adhesion molecule-1 (ICAM-1; CD54), resident on the surface of naive human T cells, to influence differentiation was investigated. Costimulation of naive T cells through ICAM-1 resulted in expansive cell division, high interleukin-2 production, and protection from apoptosis. Prolonged culture led to outgrowth of a subpopulation of cells with a highly differentiated CD45RA- CD11a(hi) CD27- phenotype. In this respect, costimulation through ICAM-1 was similar to costimulation through CD28 and different from costimulation through leucocyte function-associated antigen-1. The CD45RA- CD11a(hi) CD27- cells responded to suboptimal stimulation through the T-cell receptor alone with a more robust proliferative response compared with naive cells from the same subject. These cells also secreted higher levels of T helper type 1 cytokines in response to lower levels of stimulation than their naive counterparts. The surface phenotype and more sensitive response characteristics suggest the creation of a memory T-cell subpopulation as a result of costimulation through ICAM-1. Finally, generation of this memory population was the result of specific costimulatory signals, and not merely because of a high number of cell divisions. These data reveal a new role for resident ICAM-1 to influence the differentiation of naive T cells.

Antigens, Differentiation, T-Lymphocyte↗

PubMed1983

Heterogeneity of B-cells.

Two rat monoclonal antibodies, NIM-R2 and NIM-R3, were prepared that only recognize B-cells in murine secondary lymphoid tissues. Both showed differential reactivity in that they reacted most strongly with nonoverlapping populations of B-cells. They also reacted differentially with some cells of the primary lymphoid tissue, recognizing 90-95% of bone marrow cells, again in a nonoverlapping manner and with NIM-R2 accounting for twice as many cells as NIM-R3. The antibody NIM-R2, but not NIM-R3, also recognized thymocytes and red blood cells. The determinant recognized by NIM-R2 is of interest because it fluctuates at four defined stages of B-cell development: pre-B to immature B, activation of mature B, differentiation of memory cells, and differentiation of antibody-secreting cells. Particularly noteworthy was the differential reactivity of NIM-R2 with virgin and memory B-cells. Those cells that stained strongly with the antibody gave excellent primary responses, but were unable to transfer secondary responses, whereas weakly stained B-cells transferred memory, but could not generate primary antibody responses in vitro. Thus NIM-R2 recognized a cell-surface determinant that presumably decreases in density as primary B-cells differentiate into memory B-cells. A survey of sIg, I-A, Fc receptors, and major glycoproteins of B-cells from spleen, Peyer's patches, mesenteric lymph nodes, and peripheral lymph nodes failed to reveal any major differences between the cells from these different lymphoid organs.

Animals↗

PubMed2004

CD8alphaalpha-mediated survival and differentiation of CD8 memory T cell precursors.

Memory T cells are long-lived antigen-experienced T cells that are generally accepted to be direct descendants of proliferating primary effector cells. However, the factors that permit selective survival of these T cells are not well established. We show that homodimeric alpha chains of the CD8 molecule (CD8alphaalpha) are transiently induced on a selected subset of CD8alphabeta+ T cells upon antigenic stimulation. These CD8alphaalpha molecules promote the survival and differentiation of activated lymphocytes into memory CD8 T cells. Thus, memory precursors can be identified among primary effector cells and are selected for survival and differentiation by CD8alphaalpha.

Animals↗

PubMed1983

Two stages of b cell memory development expressing differential sensitivity to stimulation with thymus-dependent and thymus-independent antigenic forms.

We have shown that spleen cells specifically primed to the decapeptide determinant (a.a. 103-112) of the thymus-dependent (TD) antigen, tobacco mosaic virus protein (TMVP), can be secondarily stimulated to antibody synthesis by either TD or TI forms of the decapeptide. Further, TD- and TI-responsive memory B cells consisted of overlapping populations which were indistinguishable by the specificity and isotype composition of the antibodies which they synthesized. In the present study, two functionally distinct but developmentally related memory B cell subsets were identified by their differential sensitivity to repeated in vivo stimulation with various combinations of TD and TI decapeptide antigens. One subset of memory B cells responded only to TMVP or decapeptide conjugated to succinylated human gamma-globulin (SHGG) with a strict requirement for carrier-primed theta-positive cells. Secondary challenge with these two TD antigens elicited antidecapeptide antibodies and specific memory regeneration. This TD-responsive memory B cell subset contained the precursors of a second memory B cell subset which was activated by decapeptide-Brucella abortus (TI.1 prototype), as well as by TMVP or decapeptide-SHGG. Stimulation of the second memory B cell subpopulation by decapeptide-BA (previously shown not to be dependent on conventional T cell help) was typified by differentiation into antibody-forming cells without significant memory regeneration.

Animals↗

PubMed2006

Does impaired executive functioning differentially impact verbal memory measures in older adults with suspected dementia?

The purpose of this study was to examine whether executive dysfunction differentially impacts list-learning and story recall tasks in a sample of older adults referred for suspected cognitive impairment. Older adults (N = 61) with mild cognitive impairment (MCI) or probable mild dementia, and those who did not meet criteria for diagnosis of dementia, were assessed using measures of executive function and verbal memory. Two groups were established based on performance on measures of executive function: (a) the No Executive Dysfunction group (NoED; n = 33) consisted of persons without impairment on any obtained measures of executive function; and (b) the Executive Dysfunction group (ED; n = 28) contained persons with impairment on at least one of the measures of executive function. The two groups were compared on performance on two measures of verbal memory, the California Verbal Learning Test-II (CVLT-II) and the Logical Memory (LM) subtest from the Wechsler Memory Scale-Revised (WMS-R). The NoED group performed significantly better than the ED group on the total learning and short delay free recall trials of the CVLT-II. However, there were no significant differences between the groups on the other indices of the CVLT-II (i.e., long delay free recall, recognition, recall repetitions, recall intrusions, or recognition false-positives) or on the immediate and delayed recall trials of the LM measure. These results support previous research demonstrating the impact of executive dysfunction on the acquisition of and short-delay retrieval of verbal information in older adults with suspected cognitive impairment.

Aged↗

PubMed2002

Segregation of R5 and X4 HIV-1 variants to memory T cell subsets differentially expressing CD62L in ex vivo infected human lymphoid tissue.

OBJECTIVE: The mechanisms of HIV-triggered immunodeficiency were examined by determining the segregation of R5 and X4 HIV-1 variants into memory T cell subsets expressing differentially a homing receptor, CD62L-selectin, in human lymphoid tissue. METHODS: Subpopulations of CD3 and intracellular p24 gag-positive cells in human lymphoid tissue infected ex vivo with X4 HIV-1 variant NL4-3 and R5 HIV-1 variant AD8 were analysed for expression of the T cell memory markers CD45RO and CD45RA, the T cell homing receptor for lymphoid tissue CD62L, and the HIV-1 coreceptors CCR5 and CXCR4. RESULTS: Memory CD4 T cells were the predominant targets for productive infection of lymphoid tissue ex vivo with both R5 and X4 HIV-1. R5 HIV-1 predominantly infected CD62L-negative memory T cells, which selectively express CCR5. In contrast, X4 HIV-1 variants predominantly infected CD62L+ memory T cells, although CXCR4 coreceptor was equally expressed by memory T cells of both CD62L-positive and CD62L-negative subsets. A high proportion of X4 HIV-1, but not of R5 HIV-1, productively infected T cells, displayed a CD45RA+CD45RO+ phenotype. CONCLUSION: The selective expression of the CCR5 coreceptor by CD62L-negative terminally differentiated memory T cells correlates with the preferential productive infection of these cells with the R5 HIV-1 variant. The predominance of X4 HIV-1 variants in less-differentiated memory T cells may be related to their recent activation state, as suggested by the coexpression of both CD45RA and CD45RO molecules on their surface. Differential homing of CD62L-positive and CD62L-negative cells suggests different routes of dissemination of X4 and R5 viruses.

CD4-Positive T-Lymphocytes↗

PubMed2004

Mineralocorticoid and glucocorticoid receptors and their differential effects on memory performance in people with Addison's disease.

The effects of corticosteroids on memory performance have been the subject of some controversy. Whilst many studies have shown that high levels of corticosteroids can impair memory performance, others have shown they can facilitate it. One explanation for these discrepant effects arises from the differential activation of the two types of corticosteroid receptor--the mineralocorticoid receptor (MRs) and the glucocorticoid receptor (GRs), and the function each subserves during memory formation. Studies in rats and chickens suggest that activation of the MRs is essential during sensory storage (i.e. encoding), whereas normal levels of activation of the GRs (in addition to the already activated MRs) is essential during memory consolidation and retrieval. By using a repeated measures design with nine people with Addison's disease (mean age, 37.9 years), the effects following activation of the MRs only, GRs only, and a combination of MRs/GRs, on working memory and the episodic and semantic components of declarative memory were investigated. MRs and GRs were activated using either MR specific (9 alpha fluorohydrocortisone) or GR specific (dexamethasone) exogenous steroids, respectively. The results showed that participants performed better in the Digits Backward task when both receptors were activated compared to when GRs only were activated (P<0.01). They also performed better in recall in the Hopkins Verbal Learning Test when both receptors were activated compared to when MRs only were activated (P<0.05) and GRs only were activated (P<0.01). Whilst significant effects were not consistent across memory tasks, these results lend further support to the view that balanced activation of MRs and GRs is necessary for optimal memory function in humans.

Addison Disease↗

PubMed2002

Diversity, topographic differentiation, and positional memory in human fibroblasts.

A fundamental feature of the architecture and functional design of vertebrate animals is a stroma, composed of extracellular matrix and mesenchymal cells, which provides a structural scaffold and conduit for blood and lymphatic vessels, nerves, and leukocytes. Reciprocal interactions between mesenchymal and epithelial cells are known to play a critical role in orchestrating the development and morphogenesis of tissues and organs, but the roles played by specific stromal cells in controlling the design and function of tissues remain poorly understood. The principal cells of stromal tissue are called fibroblasts, a catch-all designation that belies their diversity. We characterized genome-wide patterns of gene expression in cultured fetal and adult human fibroblasts derived from skin at different anatomical sites. Fibroblasts from each site displayed distinct and characteristic transcriptional patterns, suggesting that fibroblasts at different locations in the body should be considered distinct differentiated cell types. Notable groups of differentially expressed genes included some implicated in extracellular matrix synthesis, lipid metabolism, and cell signaling pathways that control proliferation, cell migration, and fate determination. Several genes implicated in genetic diseases were found to be expressed in fibroblasts in an anatomic pattern that paralleled the phenotypic defects. Finally, adult fibroblasts maintained key features of HOX gene expression patterns established during embryogenesis, suggesting that HOX genes may direct topographic differentiation and underlie the detailed positional memory in fibroblasts.

Cell Differentiation↗

PubMed1996

Enrichment of differentiated CD45RBdim,CD27- memory T cells in the peripheral blood, synovial fluid, and synovial tissue of patients with rheumatoid arthritis.

OBJECTIVE: To delineate in greater detail the phenotype of T cells that reside in the synovial tissue (ST) and synovial fluid (SF) of patients with rheumatoid arthritis (RA), in order to determine their precise differentiation status, and to determine whether the accumulation of these specific T cell subsets in these synovial compartments could be related to their capacity for transendothelial migration. METHODS: Lymphocytes from normal subjects or from the peripheral blood (PB), ST, and/or SF of RA patients were phenotypically analyzed by flow cytometry. Normal PB CD4+ T cells were also characterized using an in vitro assay of transendothelial migration. RESULTS: ST and SF were found to be enriched with memory (CD45RA-,CD45RO+,CD11abright,CD44bright and activated (CD69+) T cells. Moreover, ST and SF cells from RA patients were enriched in differentiated CD4+,CD45RBdim,CD27- T cells, a subset of mature memory T cells that develops after prolonged antigenic stimulation. In addition, PB of some RA patients contained an increased number of CD4+,CD45RBdim,CD27- T cells. The CD4+,CD11abright,CD44bright memory T cells, which included the CD45RBdim,CD27- more mature memory cells, exhibited an enhanced capacity for transendothelial migration that is likely to contribute to their enrichment in the rheumatoid synovium. CONCLUSION: RA patients manifest an increased number of mature memory T cells in the SF and ST, and some also have an increased number of these cells in PB that is likely to reflect chronic antigenic stimulation. The enrichment of these cells in the SF and ST reflects, in part, an enhanced capacity to migrate from the vascular space into inflamed tissue.

Arthritis, Rheumatoid↗