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B-cell kinetics in humans: rapid turnover of peripheral blood memory cells.

Information about the kinetic behavior and lifespan of lymphocytes is crucial to understanding the mechanisms that regulate processes such as immunologic memory. We have used in vivo labeling of dividing cells with 6,6-(2)H(2)-glucose, combined with cell sorting and gas-chromatography-mass spectrometry for deuterium enrichment, in order to analyze the kinetics of human total, naive, or memory B lymphocytes, separated from peripheral blood using monoclonal antibodies. We show that total blood B cells of young adults divide at an average rate of 1.9% (+/-1.0%) per day and at a similar though slightly slower rate, 1.5% (+/-1.3%) per day, in the elderly. Separation of naive and memory B cells according to expression of CD27 indicates that naive peripheral blood B cells divide slowly (0.46% per day), while memory cells proliferate more rapidly (2.66% per day). These data are compatible with the view that B-cell memory may be maintained by clones of proliferating B cells.

Adult↗

Memory capacity in large idiotypic networks.

Many models of immune networks have been proposed since the original work of Jerne [1974, Ann. Immun. (Inst. Pasteur)125C, 373-389]. Recently, a limited class of models (Weisbuch et al., 1990, J. theor. Biol 146, 483-499) have been shown to maintain immunological memory by idiotypic network interactions. We examine generalizations of these models when the networks are both large and highly connected to study their memory capacity, i.e., their ability to account for immunization to a large number of random antigens. Our calculations show that in these minimal models, random connectivities with continuously distributed affinities reduce the memory capacity to essentially nil.

Animals↗

The descent of memory T-cell subsets.

The immune system has evolved by continuously increasing its complexity to provide the host with an advantage over infectious agents. The development of immunological memory engenders long-lasting protection and lengthens the lifespan of the host. The generation of subsets of memory T cells with distinct homing and functional properties increases our defensive capabilities. However, the developmental relationship of memory T-cell subsets is a matter of debate. In this Opinion article, in light of recent developments, we suggest that it is probable that two distinct lineages comprise the memory CD8+ T-cell population generated in response to infection.

Animals↗

Durable human memory T cells quantifiable by cultured enzyme-linked immunospot assays are induced by heterologous prime boost immunization and correlate with protection against malaria.

Immunological memory is a required component of protective antimalarial responses raised by T cell-inducing vaccines. The magnitude of ex vivo IFN-gamma T cell responses is widely used to identify immunogenic vaccines although this response usually wanes and may disappear within weeks. However, protection in the field is likely to depend on durable central memory T cells that are not detected by this assay. To identify longer-lived memory T cells, PBMC from malaria-naive vaccinated volunteers who had received prime boost vaccinations with a combination of DNA and/or viral vectors encoding the multiepitope string-thrombospondin-related adhesion protein Ag were cultured in vitro with Ag for 10 days before the ELISPOT assay. Ex vivo T cell responses peaked at 7 days after the final immunization and declined substantially over 6 mo, but responses identified after T cell culture increased over the 6-mo period after the final immunization. Moreover, individual cultured ELISPOT responses at the day of challenge time point correlated significantly with degree of protection against malaria sporozoite challenge, whereas ex vivo responses did not, despite a correlation between the peak ex vivo response and magnitude of memory responses 6 mo later. This cultured assay identifies long-lasting protective T cell responses and therefore offers an attractive option for assessments of vaccine immunogenicity.

Cells, Cultured↗

[IgM and IgG rosette formation in the primary and secondary immune response in the system of syngeneic transfer of spleen cells].

In the system of syngenous transfer of cells a study was made of the dynamics of IgM- and IgG- of the rosette-froming cells of the spleen in the primary and secondary immune response in mice of the CBA inbred strain immunized with sheep erythrocytes. It was shown that in prolongation of the interval between donor immunization and the transfer of cells to the recipient with his simultaneous immunization for up to 40 days there occurred an increase of the IgG-memory; as to IgM memory-it is expressed with shorter intervals. It is supposed that rosette-forming cells were not bearers of immunological memory.

Animals↗

Decrease in memory (CDw29-high) cerebrospinal fluid cells from acute MS patients.

The CD45R (2H4) and CDw29 (4B4) molecules are probably involved in the regulation of immunological memory: CD45R functionally defines naive or virgin cells (prior to activation by exposure to antigen), while CDw29 characterizes previously activated (memory) cells. By means of two-colour fluorescence analysis, we studied CD4 and CD8, CD45R and CD4 and CD8 CDw29 cells from the cerebrospinal fluid (CSF) of 27 acute (MSa), and 10 stable (MSs) multiple sclerosis (MS) patients. We also compared 17 patients affected with various non-inflammatory (OND) diseases of the central nervous system (CNS). The most striking finding was the increased percentage of CD4+CD29-, CD4+CD45R- and CD8+CD45R- cells and the decreased percentage of CD4-CDw29+ and CD8- CDw29+ subsets in MSa patients compared to OND and MSs populations. These data suggest a decrease in memory cells (CDw29+) during the acute phase of MS. The modulation of CDw29 receptor could play a role in the genesis of acute MS attacks.

Adolescent↗

Regulation of aged humoral immune defense against pneumococcal bacteria by IgM memory B cell.

Elderly persons have a high incidence of lethal infections by encapsulated bacteria. However, mechanisms involved in their poor defense and maintenance of immunological memory have been poorly understood. The present study characterized the population of B cells known as IgM memory B cell compartment and their response by pneumococcal vaccine in elderly people. CD27+ memory B cells, particularly IgD+IgM+CD27+ IgM memory B cells, had dramatically declined in the aged. Their Ig syntheses by B cells and the differentiation into plasma cells were diminished in vitro compared with those in adults. A rise of anti-pneumococcal IgM in sera of elderly persons was found with lower levels compared with those in adults after pneumococcal vaccination. Although diminished function itself of aged B cells surely exist, decline of the IgM memory B cell pool is expected to result in a poor humoral immunity against pneumococcal infection in elderly people.

Adult↗

[Immunologic properties of purified and complex preparations of group-B meningococcal polysaccharide].

The complex preparations of group B meningococcal polysaccharide have been found to be capable of inducing primary immune response in mice, while purified group B polysaccharide has proved to be immunologically inert. As revealed in this investigation, the intravenous injection to mice of the optimum doses of the complex preparation of group B polysaccharide leads to the increased number of specific B-antibody-forming cells in their spleens and to a rise in B-antibody titers in their sera; besides, the time course of the process has been studied. Both preparations have been found capable of forming the immunological memory in mice if booster immunization is made with the complex preparation of group B polysaccharide. The immunological inertness of purified group B polysaccharide is attributed, supposedly, to the action of some specific suppressor mechanism. Considering the pronounced antigenic activity of the complex preparation of group B polysaccharide and the insignificant admixture of endotoxin in this preparation, the suitability of its future use as vaccine for the prophylaxis of meningitis caused by group B meningococcus is indicated and the tentative immunization schedules are discussed.

Animals↗

Neonate-primed CD8+ memory cells rival adult-primed memory cells in antigen-driven expansion and anti-viral protection.

Immunizations early in life, when the host is most susceptible to infection, allow protective immunological memory to develop. Decreasing the dose of Cas-Br-E murine leukemia virus when priming neonatal mice results in adult-like, Type 1 protective responses, but the resulting memory cell populations are smaller than after adult priming. After secondary challenge, virus-specific CD8+ memory cell populations expand twice as much in neonate-primed mice as in adult-primed mice. We found that when equivalent numbers of virus-specific cells were transferred into virus-susceptible mice, protection from disease was similar whether donor, immune mice were primed as neonates or adults, and IL-4 did not alter in vivo virus-specific CD8+ memory cell effector function. Hence, neonate-primed CD8+ cells develop into memory cells that rival adult-primed cells in proliferation and effector function.

Animals↗

IL-15 is a growth factor and an activator of CD8 memory T cells.

Memory lymphocytes, arising from naïve lymphocytes after antigenic stimulation and being long-lived, are the cellular basis for immunological memory. Recent studies of CD8 T cells suggest that generation of CD8 memory T cells requires the engagement of T cell antigen receptors (TCR) with antigen, yet the maintenance of CD8 memory T cells appears to be dependent on cytokines, such as IL-15, independent of TCR. Although considerable progress has been made in understanding the molecular and cellular events of TCR-induced differentiation and proliferation in the past decade, less is known about the mechanisms of IL-15 action. From a kinetic and comparative analysis of the responses of memory phenotype CD8 T cells to IL-15 and TCR stimulation in vitro, we found that IL-15 and anti-CD3 induce highly similar responses in memory phenotype CD8 T cells as measured by general gene expression profiles, synthesis of effector molecules (IFNgamma, TNFbeta, granzyme B and perforin), induction of cytotoxicity, and cellular proliferation. These findings indicate that IL-15 is not only a growth factor but also an antigen-independent activator for CD8 memory T cells.

Animals↗

Characterization of alloimmune memory in a sponge.

Alloimmune memory, revealed by consistently accelerated second-set graft rejection in contrast to unrelated third-party reactions, has been reported in four species of marine sponge. Allogeneic tissue of the marine sponge, Callyspongia diffusa was grafted/parabiosed to examine critically the essential features of alloimmune memory in this member of the least complex major metazoan phylum. Although sponges lack an organized circulatory system, the immunologic memory spreads rapidly through body tissues. Heightened reactivity persisted for only 3 yo 4 wk after primary sensitization. This appears to constitute a major difference from the long-term alloimmune memory found among vertebrates. This limited duration of memory, however, is apparently sufficient for the individual sponge to cope with repeated challenges to its integrity.

Animals↗

CD8 cell division maintaining cytotoxic memory occurs predominantly in the bone marrow.

Long-term persistence of Ag-experienced CD8 cells, a class of T lymphocytes with cytotoxic function, contributes to immunological memory against intracellular pathogens. After Ag clearance, memory CD8 cells are maintained over time by a slow proliferation, primarily cytokine driven. In this article, we show that the bone marrow (BM) is the crucial organ where such basal division of memory CD8 cells occurs. BM memory CD8 cells contain a higher percentage of proliferating cells than their corresponding cells in either spleen or lymph nodes from C57BL/6 mice. This occurs both in the case of memory-phenotype CD44(high) CD8 cells and in the case of Ag-specific memory CD8 cells. Importantly, the absolute number of Ag-specific memory CD8 cells dividing in the BM largely exceeds that in spleen, lymph nodes, liver, and lung taken together. In the BM, Ag-specific memory CD8 cells express lower levels of CD127, i.e., the alpha-chain of IL-7R, than in either spleen or lymph nodes. We interpret these results as indirect evidence that Ag-specific memory CD8 cells receive proliferative signals by IL-7 and/or IL-15 in the BM and propose that the BM acts as a saturable "niche" for the Ag-independent proliferation of memory CD8 cells. Taken together, our novel findings indicate that the BM plays a relevant role in the maintenance of cytotoxic T cell memory, in addition to its previously described involvement in long-term Ab responses.

Adoptive Transfer↗

Validation of serological correlate of protection for meningococcal C conjugate vaccine by using efficacy estimates from postlicensure surveillance in England.

Meningococcal C conjugate (MCC) vaccines were licensed on the basis of serological correlates of protection without efficacy data. The original correlate of protection was established by using a serum bactericidal antibody assay (SBA) with human complement (hSBA), with titers > or =4 predicting protection. However, the antibody data supporting licensure were largely generated by SBA with rabbit complement (rSBA), which gives higher titers than hSBA. While rSBA titers > or =128 reliably predict protection, as measured by hSBA, sera with rSBA titers in the range of 8 to 64 may not have hSBA titers > or =4. For rSBA titers in this equivocal range, a fourfold rise pre- to postvaccination with the MCC vaccine and/or a characteristic booster response to a polysaccharide challenge was proposed as a correlate of protection. To validate this proposed rSBA correlate, age-specific efficacy estimates for MCC vaccines obtained from postlicensure surveillance in England were compared with the efficacy predicted by the percentage of individuals in these age groups with rSBA titers above different cutoffs at 4 weeks and at 7 to 9 months after vaccination with the MCC vaccine. The average time since vaccination in the cohorts in whom efficacy was measured ranged from 8 to 10 months. The rSBA cutoff of > or =128 was shown to significantly underestimate efficacy, with rSBA cutoffs of > or =4 or > or =8 at 4 weeks postvaccination with the MCC vaccine being the most consistent with observed efficacy. When the levels obtained 7 to 9 months postvaccination with the MCC vaccine were used, all rSBA cutoffs significantly underestimated efficacy, suggesting that continuing protection is less dependent on the SBA level at the time of exposure but is more reliant on immunologic memory.

Child↗

Kinetics of immunosuppression of sporozoite-induced immunity by Mycobacterium bovis BCG.

The data reported in this study demonstrate that the vaccination of NIH/Nmri mice with viable Mycobacterium bovis BCG organisms induces a state of immunosuppression that renders the recipient animals incapable of a protective immune response to the malaria sporozoite vaccine. The expression of this altered protective immune response is dependent upon the dosage of the two live vaccines, as well as upon the sequence of their administration. Data presented here show that the skin test responses (Arthus and delayed type) of BCG-vaccinated mice do not correlate with the suppression of sporozoite immunity. Evidence is also presented to support the hypothesis that the abrogated immune response to sporozoite vaccination induced by BCG is a result of a loss of immunological memory.

Animals↗

Dose dependency of antibody response in infants and children to pneumococcal polysaccharides conjugated to tetanus toxoid.

Three injections of tetravalent pneumococcal polysaccharide-tetanus toxoid conjugate vaccine (PncT) were given to infants at 2, 4 and 6 months of age simultaneously with diphtheria-tetanus-pertussis and Haemophilus influenzae type b-tetanus toxoid conjugate vaccines. Three doses (1, 3 or 10 microg) of polysaccharides were used. Children were boosted with unconjugated polysaccharide vaccine at 14 months of age. No dose dependency was seen after primary immunization. However, booster response to three vaccine serotypes was highest in the group primed with the lowest dose of conjugate vaccine. As the magnitude of the response to booster may be related to the number of polysaccharide-specific memory B cells, we hypothesize that the 10 microg dose of the tetravalent conjugate vaccine is too high for optimal induction of immunologic memory.

Antibodies, Bacterial↗

Increased central memory T cells in patients with chronic pancreatitis.

BACKGROUND/AIMS: A dysregulated immune response has been suggested to be important for the pathogenesis of chronic pancreatitis (CP). Formation of immunological memory is based on the differentiation of naive T lymphocytes to memory T lymphocytes after exposure to antigens and specific cytokines. The aim of this study was to analyze peripheral blood mononuclear cells (PBMCs) in patients with CP for different T lymphocyte subsets including naive and memory T cells. METHODS: PBMCs from 9 patients who had undergone pancreatic resection due to CP, 9 CP patients who had not been resected and 9 healthy controls were analyzed by flow cytometry. RESULTS: Patients with CP had a skewed distribution of T lymphocytes, with an increased level of CCR7+/CD45RA- central memory T lymphocytes compared to healthy controls. Nonresected CP patients and subjects who had undergone pancreatic resection due to CP had similar levels of central memory T lymphocytes. CONCLUSION: Our results indicate that the dysregulation of the immune system in chronic pancreatitis seems to persist even after removal of large parts of the local inflammatory site. We suggest that the increase of central memory T lymphocytes may be important for maintaining the inflammatory process in chronic pancreatitis.

Adult↗

Local and systemic immune response to orally administered liposome-associated soluble S. mutans cell wall antigens.

The aim of the present study was to develop an immunization procedure which preferentially stimulated the IgA system of rats, with release of IgA in secretions. Rats immunized by intragastric route with liposome-associated soluble antigen extracted from Streptococcus mutans cell wall, showed a significantly higher IgA (and IgG) response than did rats injected with the soluble antigen alone. In saliva, maximal antibody titres were obtained 11 days after the beginning of intubations for IgA, and 16 days for IgG. After a booster immunization, the secondary response occurred very quickly in saliva and, like the primary response, it was almost exclusively of the IgA class. This demonstrates, on one hand the existence of immunological memory in the IgA system and, on the other, the efficiency of liposomes as insoluble adjuvants in eliciting an immunological response.

Administration, Oral↗

Identification of differentially expressed genes in human memory (CD45RO+) CD4+ T lymphocytes.

The precise nature and development of the memory (CD45RO+) CD4+ T lymphocytes remain unknown. In this study, we analyzed differential gene expression of human memory CD4+ T lymphocytes in relation to their naive counterparts. A suppression subtractive hybridization technique was used to isolate and clone differentially expressed genes in the memory subset with respect to the naive subset. We screened approximately 300 clones by dot blot analysis and sequenced 23 differentially expressed clones. GenBank sequence homology search showed that these clones included genes for transcription factors, enzymes and immunomodulatory molecules. Differential expression of a subset of these genes was further confirmed by RT-PCR and densitometric analysis revealed that they were expressed five to eightfold more in memory than naive CD4+ T lymphocytes. Collectively, these results suggest that multiple genes with different functions contribute to the development of immunological memory in human T lymphocytes.

CD4-Positive T-Lymphocytes↗