Maintenance Of Immunological Memory Research Articles

COMPARISON OF THE PRIMARY AND SECONDARY HUMORAL IMMUNE RESPONSE TO VACCINATION BY “PRIORIX”

Abstract. Twenty healthy children were vaccinated, and then in a 5 years they were revaccinated with Priorix (measles, mumps, rubella vaccine), according to the national immunization calendar. The aim of the study was to observe and compare the shaping and maintenance of immunological memory. Specific IgM, IgA, IgG antibodies in serum, and their subclasses as well as antibodies avidity were tested by ELISA. It was demonstrated that IgM, IgG, and IgA antibodies shaped primary immune response to Priorix. Booster-effect was found in IgG and IgA antibodies in response to revaccination. Low avidity of antibodies in primary immune response changed to the high avidity (60–70%) antibodies of memory response to measles and rubella, and remained low for antimumps antibodies. IgG3 subclass was predominant, and IgG1 and IgG4 subclasses were involved in primary immune response. At the stage of immunological memory IgG1 was predominanted and IgG3 and IgG4 became minor.

Serial Transfer of Single-Cell-Derived Immunocompetence Reveals Stemness of CD8+ Central Memory T Cells

Maintenance of immunological memory has been proposed to rely on stem-cell-like lymphocytes. However, data supporting this hypothesis are focused on the developmental potential of lymphocyte populations and are thus insufficient to establish the functional hallmarks of stemness. Here, we investigated self-renewal capacity and multipotency of individual memory lymphocytes by invivo fate mapping of CD8(+) Tcells and their descendants across three generations of serial single-cell adoptive transfer and infection-driven re-expansion. We found that immune responses derived from single naive T(Tn) cells, single primary, and single secondary central memory T (Tcm) cells reached similar size and phenotypic diversity, were subjected to comparable stochastic variation, and could ultimately reconstitute immunocompetence against an otherwise lethal infection with the bacterial pathogen Listeria monocytogenes. These observations establish that adult tissue stem cells reside within the CD62L(+) Tcm cell compartment and highlight the promising therapeutic potential of this immune cell subset.

Characterization of pandemic influenza immune memory signature after vaccination or infection.

The magnitude, quality, and maintenance of immunological memory after infection or vaccination must be considered for future design of effective influenza vaccines. In 2009, the influenza pandemic produced disease that ranged from mild to severe, even fatal, illness in infected healthy adults and led to vaccination of a portion of the population with the adjuvanted, inactivated influenza A(H1N1)pdm09 vaccine. Here, we have proposed a multiparameter quantitative and qualitative approach to comparing adaptive immune memory to influenza 1 year after mild or severe infection or vaccination. One year after antigen encounter, severely ill subjects maintained high levels of humoral and polyfunctional effector/memory CD4⁺ T cells responses, while mildly ill and vaccinated subjects retained strong cellular immunity, as indicated by high levels of mucosal homing and degranulation markers on IFN-γ⁺ antigen-specific T cells. A principal component analysis distinguished 3 distinct clusters of individuals. The first group comprised vaccinated and mildly ill subjects, while clusters 2 and 3 included mainly infected individuals. Each cluster had immune memory profiles that differed in magnitude and quality. These data provide evidence that there are substantial similarities between the antiinfluenza response that mildly ill and vaccinated individuals develop and that this immune memory signature is different from that seen in severely ill individuals.

Essential role for autophagy in the maintenance of immunological memory against influenza infection.

Vaccination has been the most widely used strategy to protect against viral infections for centuries. However, the molecular mechanisms governing the long-term persistence of immunological memory in response to vaccines remain unclear. Here we show that autophagy plays a critical role in the maintenance of memory B cells against influenza virus infection. Memory B cells displayed elevated levels of basal autophagy with increased expression of genes that regulate autophagy initiation or autophagosome maturation. Mice with B cell-specific deletion of Atg7 (B/Atg7−/−) showed normal primary antibody responses after immunization against influenza, but failed to generate protective secondary antibody responses when challenged with influenza viruses, resulting in high viral loads, widespread lung destruction and increased fatality. Our results suggest that autophagy is essential for the survival of virus-specific memory B cells and the maintenance of protective antibody responses required to combat infections.

B-Cell Responses to Pregnancy-Restricted and -Unrestricted Plasmodium falciparum Erythrocyte Membrane Protein 1 Antigens in Ghanaian Women Naturally Exposed to Malaria Parasites

Protective immunity to Plasmodium falciparum malaria acquired after natural exposure is largely antibody mediated. IgG-specific P. falciparum EMP1 (PfEMP1) proteins on the infected erythrocyte surface are particularly important. The transient antibody responses and the slowly acquired protective immunity probably reflect the clonal antigenic variation and allelic polymorphism of PfEMP1. However, it is likely that other immune-evasive mechanisms are also involved, such as interference with formation and maintenance of immunological memory. We measured PfEMP1-specific antibody levels by enzyme-linked immunosorbent assay (ELISA) and memory B-cell frequencies by enzyme-linked immunosorbent spot (ELISPOT) assay in a cohort of P. falciparum-exposed nonpregnant Ghanaian women. The antigens used were a VAR2CSA-type PfEMP1 (IT4VAR04) with expression restricted to parasites infecting the placenta, as well as two commonly recognized PfEMP1 proteins (HB3VAR06 and IT4VAR60) implicated in rosetting and not pregnancy restricted. This enabled, for the first time, a direct comparison in the same individuals of immune responses specific for a clinically important parasite antigen expressed only during well-defined periods (pregnancy) to responses specific for comparable antigens expressed independent of pregnancy. Our data indicate that PfEMP1-specific B-cell memory is adequately acquired even when antigen exposure is infrequent (e.g., VAR2CSA-type PfEMP1). Furthermore, immunological memory specific for VAR2CSA-type PfEMP1 can be maintained for many years without antigen reexposure and after circulating antigen-specific IgG has disappeared. The study provides evidence that natural exposure to P. falciparum leads to formation of durable B-cell immunity to clinically important PfEMP1 antigens. This has encouraging implications for current efforts to develop PfEMP1-based vaccines.

FRI0035 Bone marrow stroma cells as organizers of immunological memory

BackgroundA key property of the vertebrate immune system is its ability to establish and maintain long-lasting protection and fast, adapted reaction against previously encountered pathogens, the immunological memory. However, immunological...

IMprinting of PAthogenic Memory in Berlin

Immunological memory is not only protective against recurrent pathogens but it also contributes to the pathogenesis of chronic inflammation, especially in rheumatic diseases. The Joint Meeting of the Henry Kunkel Society (HKS) and the Research Consortium IMPAM (IMprinting of the PAthogenic Memory for rheumatic inflammation), which took place in June 2012 in Berlin, was devoted to discussing the basic mechanisms involved in the generation and maintenance of immunological memory, as well as the implications of immunological memory for the pathogenesis and therapy of rheumatic diseases, cancer and vaccine development as outlined in this Meeting Report.

CD49b/CD69-Dependent Generation of Resting T Helper Cell Memory

In the absence of antigen, memory T helper (Th) cells are maintained in a resting state. Recently it has been shown that bone marrow (BM) is a major reservoir of resting memory Th cells. In a given immune response, less than 10% of the activated CD4 T cells are recruited to the pool of resting BM memory Th cells. Here we review recent evidence that CD69 and CD49b control homing of memory Th cell precursors to the BM. During the effector phase of an immune response, about 10% of activated CD4 T cells in the spleen express both CD69 and CD49b, and thus qualify as precursors of resting memory Th cells of BM. Loss or blockade of CD69 and CD49b expression on CD4 T cells impairs the generation of resting memory Th cells in the BM. Moreover, in the absence of BM memory Th cells in CD69-deficient mice, T-cell help for B cells is impaired, confirming the central role of BM memory Th cells in the maintenance of immunological memory.

Chronic Bystander Infections and Immunity to Unrelated Antigens

Chronic infections with persistent pathogens such as helminths, mycobacteria, Plasmodium, and hepatitis viruses affect more than a third of the human population and are associated with increased susceptibility to other pathogens as well as reduced vaccine efficacy. Although these observations suggest an impact of chronic infections in modulating immunity to unrelated antigens, little is known regarding the underlying mechanisms. Here, we summarize evidence of the most prevalent infections affecting immunity to unrelated pathogens and vaccines, and discuss potential mechanisms of how different bystander chronic infections might impact immune responses. We suggest that bystander chronic infections affect different stages of host responses and may impact transmission and recognition of other pathogens, innate immune responses, priming and differentiation of adaptive effector responses, as well as the development and maintenance of immunological memory. Further understanding of the immunological effects of coinfection should provide opportunities to enhance vaccine efficacy and control of infectious diseases.

Signals controlling rest and reactivation of T helper memory lymphocytes in bone marrow.

Established views on the maintenance of immunological memory have been challenged recently by the description of memory plasma cells and memory T helper (Th) lymphocytes residing in the bone marrow (BM) in dedicated survival niches, resting in terms of proliferation and migration. While memory plasma cells are no longer reactive to antigen, memory Th lymphocytes are in a state of attentive rest, and can be reactivated fast and efficiently. Here, we discuss the signals controlling these resting states, which the memory lymphocytes receive from their microenvironment.

Maintenance of CD4+ T-cell memory and HIV persistence: keeping memory, keeping HIV

The present review summarizes the current challenges for the design of new therapeutic strategies toward HIV eradication in individuals receiving suppressive highly active antiretroviral therapy (HAART). We will focus on the experimental evidence suggesting that immunological mechanisms involved in the generation and maintenance of memory CD4+ T cells are also responsible for the establishment and persistence of a stable reservoir for HIV. Recent studies performed on clinical samples obtained from virally suppressed HIV-infected individuals indicate that T-cell survival and homeostatic proliferation, two major mechanisms involved in the maintenance of immunological memory, contribute to the persistence of latently infected memory CD4+ T cells. Thus, the long lifespan characteristic of the HIV reservoir is likely a consequence of the capacity of the immune system to generate and maintain memory CD4+ T cells for a long period. These findings suggest that strategies aimed at reducing the pool of latently infected cells should interfere with the survival pathways responsible for the long-term maintenance of memory CD4+ T cells. Because memory CD4+ T cells are critical for appropriate immune defense, targeted approaches are needed to interfere only with the long-term survival of discrete fractions of memory T cells carrying proviral DNA.

Theoretical analysis of the evolution of immune memory.

BackgroundThe ability of an immune system to remember pathogens improves the chance of the host to survive a second exposure to the same pathogen. This immunological memory has evolved in response to the pathogen environment of the hosts. In vertebrates, the memory of previous infection is physiologically accomplished by the development of memory T and B cells. Many questions concerning the generation and maintenance of immunological memory are still debated. Is there a limit to how many memory cells a host can generate and maintain? If there is a limit, how should new cells be incorporated into a filled memory compartment? And how many different pathogens should the immune system remember?ResultsIn this study, we examine how memory traits evolve as a response to different pathogen environments using an individual-based model. We find that even without a cost related to the maintenance of a memory pool, the positive effect of bigger memory pool sizes saturates. The optimal diversity of a limited memory pool is determined by the probability of re-infection, rather than by the prevalence of a pathogen in the environment, or the frequency of exposure.ConclusionsRelating immune memory traits to the pathogen environment of the hosts, our population biological framework sheds light on the evolutionary determinants of immune memory.

Organization and maintenance of immunological memory by stroma niches

Immunological memory is still one of the enigmas of modern immunology. We poorly understand the generation of memory cells from their precursors, the lifestyle of memory cells or their maintenance, reactivation and termination. Here, we discuss the recent evidence suggesting that memory plasma cells, as defined in this review, and memory Th cells are maintained in the bone marrow, resting (in terms of proliferation) in survival niches organized by dedicated stroma cells, which control the homeostasis of immunological memory.

Analysis of memory T cells in the human paracoccidioidomycosis before and during chemotherapy treatment

Memory T cell populations in patients with paracoccidioidomycosis (PCM) were analyzed before and after chemotherapy treatment. Peripheral blood mononuclear cells (PBMC) collected from patients infected by Paracoccidioides brasiliensis or from non-infected individuals were stimulated in vitro with either membrane and extra-cellular antigens (MEXO) or yeast cell antigen preparation (PbAg) of P. brasiliensis. An increase in the level of CD4 + memory T cells was determined in PBMC from PCM patients before (NT) and after treatment (TR) and in those with PCM relapsed (RE) compared to that from non-infected controls (NINF). The CD8 + memory T cells were increased in PBMC from RE patients stimulated with MEXO, but not in NT or TR. The distribution of memory B cells did not differ between NT and TR patients, while a significant elevation was determined in RE patients and higher antibody levels were also detected. The cytokine analysis showed low production of IFN-γ by cells from RE patients compared with NT or TR patients. In contrast, high production of IL-4 was detected in NT and RE patients, and moderate levels were produced by RE patients. These results suggest that IFN-γ production may participate in the maintenance of immunological memory in the acquired protection against P. brasiliensis infection and this data can contribute to future development of successful treatment of PCM to avoid relapsing.

Immunization of mice with DNA coding for the variable regions of anti-idiotypic antibody generates antigen-specific response

Understanding the mechanisms of generation and maintenance of immunological memory is crucial for rational vaccine design. A hypothesis known as relay hypothesis was earlier proposed which explains the maintenance of immunological memory through interaction of idiotypic and anti-idiotypic lymphocytes. In the present study, we have shown that immunization with rinderpest virus hemagglutinin protein specific anti-idiotypic antibody (Ab(2)v(beta)) DNAs coding for heavy and light chains generates antigen-specific antibody and T cell responses as well as Ab1 specific T cell response. We further show that boosting with the recombinant Ab(2)-vbeta proteins generates B and T cell memory response specific for antigen in anti-id DNA primed mice. This study provides experimental evidence for perpetuation of immunological memory through idiotypic network interactions.

Clinical utilization of chemokines to combat cancer: the double-edged sword

Chemokines are a small group of related chemo-attractant peptides that play an essential role in the homeostatic maintenance of the immune system. They control the recruitment of cells needed for the induction and activation of innate and adaptive immune responses. However, tumors also utilize chemokines to actively progress and evade immunosurveillance. In fact, chemokines are involved directly or indirectly in almost every aspect of tumorigenesis. They mediate survival and metastatic spread of tumors, promote new blood vessel formation (neovascularization) and induce an immunosuppressive microenvironment via recruitment of immunosuppressive cells. As a result, a number of therapeutic strategies have been proposed to target almost every step of the chemokine/chemokine receptor involvement in tumors. Yet, despite occasional success stories, most of them appear to be ineffective or impractical, presumably due to ‘nonspecific’ harm of cells needed for the elimination of tumor escapees and maintenance of immunological memory. The strategy would only be effective if it also promoted antitumor adaptive immune responses capable of combating a residual disease and tumor relapse.

The relevance of cytokines for development of protective immunity and rational design of vaccines

Cytokines are key regulators of the immune system that shape innate and adaptive immune responses. An adequate balance of the cytokine environment is critical to achieve protective immunity and to avoid immunopathology. Present knowledge allows a deeper understanding of the cytokine network and their sometimes conflicting roles in the development of immune responses, as well as their relevance in the establishment and maintenance of immunological memory. New insights have been gained into the role of different T cell subsets for protection against infection or tumor growth. The incorporation of cytokines as molecular adjuvants in vaccines has been attempted to strengthen vaccine-induced immune responses, and as a rational approach to modulate cytokine milieu in vivo and tailor host immunity for specific situations. These approaches have been tried in experimental models and veterinary species, and a few of them have entered into clinical trials. However, manipulating the cytokine network to modulate immune responses is not a simple task, because cytokine functions are complex and the final effects on the immune response will depend on timing and length of exposure, cell(s) targeted and other cytokines present in the same microenvironment. Here, we will review our present understanding on the role of cytokines in the development of effector and memory T cell responses. Also the potential use of cytokines as molecular adjuvant for vaccines against infectious diseases and cancer will be revised.

Maintenance of antigen‐specific immunological memory through variable regions of heavy and light chains of anti‐idiotypic antibody

Immunological memory is characterized by a quick and enhanced immune response after re-exposure to the same antigen. To explain the mechanism involved in generation and maintenance of immunological memory, we had earlier proposed a hypothesis involving the relay of memory by idiotypic and anti-idiotypic B cells. The peptidomimic present in the hypervariable region of anti-idiotypic antibody was hypothesized to carry forward immunological memory. In the present work, we provide evidence supporting a role for the anti-idiotypic antibody in eliciting antigen-specific B-cell and T-cell responses. Employing the idiotypic monoclonal antibody (Ab(1)) specific for haemagglutinin (H) protein of rinderpest virus, Ab(2beta) was generated, which possesses an internal image of the H protein in the region between amino acids 527 and 556. We demonstrate that antigen-specific memory is perpetuated by immunization with Ab(2), as shown by maintenance of antigen-specific T-cell responses upon restimulation in vitro of Ab(2) immune splenocytes by antigen-presenting cells expressing H protein or pulsed with H-protein-derived peptides. We have also shown that boosting with antigen-specific anti-idiotypic B cells generates a memory response in antigen-primed mice. Evidence has been provided for the existence of an antigen-specific B-cell idiotypic network in the body that supports the perpetuation of immunological memory as proposed in the relay hypothesis.

Generation and Maintenance of Mucosal Memory B Cell Responses?

The mucosal immune system comprises B cells that can mount potent antibody responses against a variety of mucosal pathogens. Mucosal B cell responses can play a decisive role in protection against mucosal pathogens. Induction of mucosal B cell responses can be achieved through mucosal vaccination. However, mucosal administration of antigens without the use of adjuvants or delivery systems can lead to tolerance rather than immunity, and thus considerable efforts have been focused on development of effective immunopotentiating adjuvants and delivery systems. However, because the ultimate goal of vaccination is the induction and maintenance of immunological memory, the underlying mechanisms for induction of long-term mucosal B cell memory need to be analyzed for the selection of appropriate adjuvants. Moreover, as the antigen unspecific innate immune system invoked by adjuvants contributes significantly to the development of antigen-specific B cell responses, and presumably B cell memory, optimal interaction of B cells with cellular components of the innate immune system is required. To better understand the mechanisms that lead to the induction of mucosal antibody responses, antibodies against single epitopes from specific B cell clones as opposed to antibodies against large poly proteins from multiple B cell clones can be studied. This review deals with the concept of mucosal B cell memory with special emphasis on efforts to devise effective prophylactic or therapeutic vaccines.

EBV-associated mononucleosis leads to long-term global deficit in T-cell responsiveness to IL-15

In mice, interleukin-7 (IL-7) and IL-15 are involved in T-cell homeostasis and the maintenance of immunologic memory. Here, we follow virus-induced responses in infectious mononucleosis (IM) patients from primary Epstein-Barr virus (EBV) infection into long-term virus carriage, monitoring IL-7 and IL-15 receptor (IL-R) expression by antibody staining and cytokine responsiveness by STAT5 phosphorylation and in vitro proliferation. Expression of IL-7Ralpha was lost from all CD8+ T cells, including EBV epitope-specific populations, during acute IM. Thereafter, expression recovered quickly on total CD8+ cells but slowly and incompletely on EBV-specific memory cells. Expression of IL-15Ralpha was also lost in acute IM and remained undetectable thereafter not just on EBV-specific CD8+ populations but on the whole peripheral T- and natural killer (NK)-cell pool. This deficit, correlating with defective IL-15 responsiveness in vitro, was consistently observed in patients up to 14 years after IM but not in patients after cytomegalovirus (CMV)-associated mononucleosis, or in healthy EBV carriers with no history of IM, or in EBV-naive individuals. By permanently scarring the immune system, symptomatic primary EBV infection provides a unique cohort of patients through which to study the effects of impaired IL-15 signaling on human lymphocyte functions in vitro and in vivo.