Immune memory,immune oblivion: A lesson from Funes the memorious

We commonly think of the immune system as having a memory. However, memory is always accompanied by a complementary process of oblivion. Is there immune oblivion? In this theoretical paper, I address this question and suggest that oblivion is an integral aspect of memorization. In this context, I suggest that immune memory is an orchestration of reversible and irreversible processes of biological computation through feedback loops. Drawing on the linguistic metaphor, I inquire into the implications of this idea for a better understanding of immune memory and immune deficiency among the elderly.     

Persistence of viral infections on the population level explained by an immunoepidemiological model

We consider a mathematical model of viral spread in a population based on an immune response model embedded in an epidemic network model. The immune response model includes virus load and effector and memory T cells with two possible outcomes depending on parameters: (a) virus clearance and establishment of immune memory and (b) establishment of a non-zero viral presence characterized with increased T-cell concentrations. Isolated individuals can have different immune system parameters and, after a primary infection, can either return to the infection-free state or develop persistent or chronic infection. When individuals are connected in the network, they can reinfect each other. We show that the virus can persist in the epidemic network for indefinite time even if the whole population consists of individuals that are able to clear the virus when isolated from the network. In this case a few individuals with a relatively weak immune response can maintain the infection in the whole population. These results are in contrast to implications of classical epidemiological models that a viral epidemic will end if there is no influx of new susceptibles and if individuals can become immune after infection.     

On modelling of immune memory mechanisms

In human body, the acquired protection against illness is a biological property known as immunological memory. Different mechanisms for immunological memory are proposed and modeled. The first mechanism is the persisting antigen (Ag) where parts of the Ag are anticipated to persist on some Ag presenting cells. A novel application of the Hsu et al.'s model allows stable low Ag density equilibrium state. This state will correspond to the persisting Ag mechanism for the immune memory. The second is idiotypic and extremal mechanisms where mathematical models showed that a memory state could arise in this case. Finally, a simple model is given which shows that competition between effectors may contribute to the memory state.     

Identification of different tumor escape mechanisms in several metastases from a melanoma patient undergoing immunotherapy

The cytotoxic activity of T cells selects the outgrowth of tumor cells that escape from immune surveillance by different strategies. The different mechanisms that interfere with immune recognition and limit vaccination efficiency are still poorly understood. We analysed six cell lines established from different metastases of melanoma patient UKRV-Mel-20 for specific characteristics known to have an impact on the tumor-T cell interaction: (1) alterations in the HLA class I phenotype, (2) expression of Fas/CD95, and (3) expression of specific cytokines and chemokines. One of the cell lines, UKRV-Mel-20f, exhibited an HLA class I haplotype loss and just this cell line was also characterised by the expression of Fas/CD95 and of relatively high levels of proinflammatory chemokines suggesting that the cytotoxic activity of tumor-infiltrating T cells might have selected the outgrowth of this tumor cell variant. All other cell lines analysed showed no alterations in HLA class I expression, but, in contrast to UKRV-Mel-20f, expressed much lower levels of Fas/CD95 and of proinflammatory chemokines and some of them produced high levels of immunosuppressive TGF-beta1. These results suggest that in patient UKRV-Mel-20, tumor cells interfere with T cell recognition by different strategies which might partially explain why this patient did not have a clinical response to an autologous tumor cell vaccine.     

记忆性T细胞的形成与特点

免疫记忆是在缺乏抗原存在的情况下,免疫系统所具有的一个特殊警觉时期.关于记忆细胞的产生和维持机理以及体内的功能调控因子如何发挥功效等方面一直以来都存在着争论.随着生物化学和基因组学的发展,记忆性T细胞的形成及特点在分子水平方面已得到了良好的解释.     

Differential expansion and survival of high and low avidity cytotoxic T cell populations during the immune response to a viral infection

The importance of high avidity CTL for the effective clearance of viral infections is now well established. Thus one would predict that the preferential activation and expansion of high avidity CTL following viral challenge and retention of these cells in the memory pool would be optimal for the immune response. However, whether this actually occurs during the immune response to viral infection is unknown. In this report I have analyzed the avidity of the CTL specific for the OVA(257-264) peptide during acute infection with a recombinant vaccinia expressing ovalbumin and in the memory population. I have found that the relative ratio of high and low avidity CTL varies over the course of an immune response. Thus CTL avidity is an important factor in the expansion and survival of CTL in vivo.     

How tumors escape immune destruction and what we can do about it

There is strong circumstantial evidence that tumor progression in cancer patients is controlled by the immune system. As will be detailed below, this conclusion is based on observations that tumor progression is often associated with secretion of immune suppressive factors and/or downregulation of MHC class I antigen presentation functions. The inference is that tumors must have elaborated strategies to circumvent an apparently effective immune response. Importantly, a tumor-specific immune response cannot be detected in most individuals. While this failure is in part technical, it also suggests that the magnitude of the immune responses to which tumors have to respond is low. This raises the concern, which is the underlying theme of this commentary, that a more robust immune response elicited by deliberate vaccination will exacerbate the rate of immune escape and nullify the potential benefits of immune-based therapies. Received: 20 March 1999 / Accepted: 3 May 1999     

Lymph node macrophages and reticulum cells in the immune response

Summary The morphology and kinetics of macrophages and reticulum cells of rat lymph nodes have been studied in relation to the immune response to a second exposure to antigen. During the first 24 h after stimulation monocyte-like exudate macrophages, including some scattered interdigitating cells (IDC), contain granules similar to those present in epidermal Langerhans cells and lymph-borne veiled cells. In this induction phase these macrophages migrate from the marginal sinus into the paracortex and during the migration they gradually transform into IDC. In the proliferation phase the paracortex is mainly populated by transitional macrophages and there are almost no typical IDC present between the lymphoblasts. In the memory phase the relative number of IDC again rapidly increases. During this period in the paracortex there are often typical IDC which contain partially digested necrotic lymphocytes, thus resembling tingible body macrophages (TBM) of the germinal centre in this respect.It is suggested that the newly arrived macrophages induce the lymphoblast reaction, while mature IDC may have an inhibitory function in the memory phase of the immune response. In this phase the phagocytic potential of IDC is clearly shown.     

Characterization and function of an E2-17 kDa (UBE2D) in an invertebrate Haliotis diversicolor supertexta

Ubiquitin-conjugating enzymes (UBE2s or E2s) are characterized by the presence of a highly conserved ubiquitin-conjugating (UBC) domain, which predominantly determines the type of ubiquitin chains and directly controls the cellular fate of the substrate. In this study, an E2 homolog was identified and functionally characterized in abalone, which we named ab-UBE2D. The full-length cDNA consists of 1005 bp with an ORF encoding a protein of 147 amino acids. The deduced amino acid sequence shows ab-UBE2D shares conserved UBC domain with other E2 proteins and belongs to class I E2 enzyme family, which are further confirmed by phylogenetic tree analysis. Real-time PCR and western blot analyses showed that ab-UBE2D was ubiquitously expressed in abalone and the expression level of ab-UBE2d was significantly induced by LPS and Poly (I:C). Immunofluorescence microscopy staining demonstrated that native ab-UBE2D was mainly distributed in the cytoplast. Ubiquitination assay showed that ab-UBE2D had ubiquitin conjugating activity to form the enzyme-(Ub)n conjugates. Taken together, these results strongly suggest that ab-UBE2D is an E2 homolog and it may be involved in the immune response of abalone, Haliotis diversicolor supertexta.     

复方五味子口服液对小鼠的药理作用

研究了复方五味子口服液对小鼠学习记忆、抗氧化和免疫功能的影响,结果表明：复方五味子口服液对D-gal所致小鼠亚急性衰老模型具有提高SOD活性和降低MDA含量的作用,有降低小鼠自主活动的作用,能提高小鼠耐缺氧能力,并且改善戊巴比妥钠所致小鼠记忆障碍,同时可明显促进小鼠淋巴细胞的增殖及网状内皮吞噬功能。     

High frequency of homozygosity of the HLA region in melanoma cell lines reveals a pattern compatible with extensive loss of heterozygosity

Malignant transformation of cells is frequently associated with abnormalities in human leukocyte antigen (HLA) expression. MHC class I loss or down-regulation in cancer cells is a major immune escape route used by a large variety of human tumours to evade antitumour immune responses mediated by cytotoxic T lymphocytes. The goal of our study was to explore HLA genotyping and phenotyping in a variety of melanoma tumour cell lines. A total of 91 melanoma cell lines were characterised for HLA class I and II genotype. In addition, 61 out of the 91 cell lines were also analysed for HLA class I and II cell surface molecule expression by flow cytometry. Unexpectedly, we found that 19.7% of the melanoma cell lines were homozygous for HLA class I genotypes, sometimes associated with HLA class II homozygosity (8.79%) and sometimes not (10.98%). The frequency of homozygosity was significantly higher compared with the control groups (1.6%). To identify the reasons underlying the high frequency of HLA homozygosity we searched for genomic deletions using eight pairs of highly polymorphic microsatellite markers covering the entire extended HLA complex on the short arm of chromosome 6. Our results were compatible with hemizygous deletions and suggest that loss of heterozygosity on chromosome arm 6p is a common feature in melanoma cell lines. In fact, although autologous normal DNA from the patients was not available and could not be tested, the retention in some cases of heterozygosity for a number of microsatellite markers would indicate a hemizygous deletion. In the rest of the cases, markers at 6p and 6q showed a single allele pattern indicating the probable loss of part or the whole of chromosome 6. These results led us to conclude that loss of heterozygosity in chromosome 6 is nonrandom and is possibly an immunologically relevant event in human malignant melanoma. Other well-established altered HLA class I phenotypes were also detected by flow cytometry that correspond to HLA class I total loss and HLA-ABC and/or specific HLA-B locus down-regulation.     

Emerging role of immune cell network in autoimmune skin disorders: An update on pemphigus,vitiligo and psoriasis

Autoimmune skin diseases are a group of disorders that arise due to a deregulated immune system resulting in skin tissue destruction. In the majority of these conditions, either autoreactive immune cells or the autoantibodies are generated against self-antigens of the skin. Although the etiology of these diseases remains elusive, biochemical, genetic, and environmental factors such as infectious agents, toxins damage the skin tissue leading to self-antigen generation, autoantibody attack and finally results in autoimmunity of skin. Immune dysregulation, which involves predominantly T helper 1/17 (Th1/Th17) polarization and the inability of regulatory T cells to regress immune response, is implicated in autoimmune skin diseases.The emerging roles of immune cells, cytokines, and chemokines in the pathogenesis of common autoimmune skin diseases like pemphigus, vitiligo, and psoriasis are discussed in this review. The main focus is on the interplay between immune cell network including the innate and adaptive immune system, regulatory cells, immune checkpoints and recently identified tissue-resident memory cells (TRMs) in disease pathogenesis and relapse. We also attempt to highlight on the immune mechanisms common to these diseases which can be targeted for designing novel therapeutics.     

Genomic instability,inflammatory signaling and response to cancer immunotherapy

Genomic and chromosomal instability are hallmarks of cancer and shape the genomic composition of cancer cells, thereby determining their behavior and response to treatment. Various genetic and epigenetic alterations in cancer have been linked to genomic instability, including DNA repair defects, oncogene-induced replication stress, and spindle assembly checkpoint malfunction. A consequence of genomic and chromosomal instability is the leakage of DNA from the nucleus into the cytoplasm, either directly or through the formation and subsequent rupture of micronuclei. Cytoplasmic DNA subsequently activates cytoplasmic DNA sensors, triggering downstream pathways, including a type I interferon response. This inflammatory signaling has pleiotropic effects, including enhanced anti-tumor immunity and potentially results in sensitization of cancer cells to immune checkpoint inhibitors. However, cancers frequently evolve mechanisms to avoid immune clearance, including suppression of inflammatory signaling. In this review, we summarize inflammatory signaling pathways induced by various sources of genomic instability, adaptation mechanisms that suppress inflammatory signaling, and implications for cancer immunotherapy.     

Parasites and immune responses: memory illusion?

Immunological memory responses to intracellular protozoa and extracellular helminths govern host resistance and susceptibility to reinfection. Humans and livestock living in parasitic disease endemic regions face continuous exposure from a very early age that often leads to asymptomatic chronic infection over their entire lifespan. Fundamental immunological studies suggest that the generation of T-cell memory is driven by tightly coordinated innate and adaptive cellular immune responses rapidly triggered following initial host infection. A key distinguishing feature of immune memory maintenance between the majority of parasitic diseases and most bacterial or viral diseases is long-term antigen persistence. Consequently, functional parasite immune memory is in a continuous, dynamic flux between activation and deactivation producing functional parasite killing or functional memory cell death. In this sense, T-cell immune memory can be regarded as "memory illusion." Furthermore, due to the finite capacity of memory lymphocytes to proliferate, continuous parasite antigen stimulation may exceed a threshold level at some point in the chronically infected host. This may result in suboptimal effector immune memory leading to host susceptibility to reinfection, or immune dysregulation yielding disease reactivation or immune pathology. The goal of this review is to highlight, through numerous examples, what is currently known about T-cell immune memory to parasites and to provide compelling hypotheses on the survival and maintenance of parasite "memory illusion." These novel concepts are discussed in the context of rationale parasite vaccine design strategies.     

Immune receptor signaling, aging, and autoimmunity

With advancing age, the immune system undergoes changes that predispose to autoimmune reactivity. Aging reduces the efficiency of physical barriers, decreasing protection against invasive pathogens, and exposing previously hidden antigens in the body's own tissues. Self-antigens acquire alterations that increase their immunogenicity. In addition, the ability of innate immunity to eliminate infectious agents deteriorates, resulting in inappropriate persistence of immune stimulation and antigen levels exceeding the threshold for the activation of B or T cells. B cell turnover is reduced and numbers of na?ve T cells decline to the advantage of increasing numbers of memory T cells. In parallel, the loss of co-stimulatory T cell molecules may increase reactivity of T cells, and render them less susceptible to downregulation. Since optimal immune reactivity requires a tight balance of transduction pathways in both T and B lymphocytes, and because these pathways are altered in systemic autoimmune diseases, we would like to propose that, with age, alterations of the immune receptor signaling machinery underlie the higher incidence of autoimmune phenomena in the elderly. Consistently, aging is associated with alterations in several components of the signaling complex in B cells, memory and na?ve T cells, and a reduced activation of several lipid rafts-associated proteins. Because the coincidence of autoimmune disease with other ailments increases the burden of disease and limits therapeutic options in the aged, further investigation of these pathways in the elderly represents a challenge that will need to be addressed in order to devise effective preventive and therapeutic interventions.     

Functional impairment of central memory CD4 T cells is a potential early prognostic marker for changing viral load in SHIV-infected rhesus macaques

In HIV infection there is a paucity of literature about the degree of immune dysfunction to potentially correlate and/or predict disease progression relative to CD4(+) T cells count or viral load. We assessed functional characteristics of memory T cells subsets as potential prognostic markers for changing viral loads and/or disease progression using the SHIV-infected rhesus macaque model. Relative to long-term non-progressors with low/undetectable viral loads, those with chronic plasma viremia, but clinically healthy, exhibited significantly lower numbers and functional impairment of CD4(+) T cells, but not CD8(+) T cells, in terms of IL-2 production by central memory subset in response to PMA and ionomycine (PMA+I) stimulation. Highly viremic animals showed impaired cytokine-production by all T cells subsets. These results suggest that functional impairment of CD4(+) T cells in general, and of central memory subset in particular, may be a potential indicator/predictor of chronic infection with immune dysfunction, which could be assayed relatively easily using non-specific PMA+I stimulation.     

A chronic viral infection model with immune impairment

In this paper, a chronic viral infection model with cell-mediated immunity and immune impairment is proposed and studied, under the assumption that the presence of the antigen can both stimulate and impair immunity. It is shown that the virus persists in the host if the basic reproductive ratio of the virus is greater than 1. The immune cells persist when there is only one positive equilibrium. The system can exhibit two positive equilibria if the basic reproductive ratio of the virus is above a threshold. This allows a bistable behavior, and the immune cells persist or die out, i.e., infection will result in disease or immune control outcome, depending on the initial conditions. By theoretical analysis and numerical simulations, we show that therapy could shift the patient from a disease progression to an immune control outcome, despite that the therapy is not necessarily lifelong. This would allow the immune response to control the virus in the long term even in the absence of continued therapy.     

Direct cross-priming by th lymphocytes generates memory cytotoxic T cell responses

Under optimal Ag stimulation, CTL become functional effector and memory T cells. Professional APCs (pAPC) are considered essential for the activation of CTL, due to their unique capacity to provide costimulation and present exogenous Ags through MHC class I molecules. In this study, we report a novel means by which Th lymphocytes acquire and present MHC class I determinants to naive CTL. Although previous studies have looked at T cell Ag presentation to activated T cells, this study presents the first example of Ag presentation by Th cells to naive CTL. We report that activated Th cells can function as effective pAPC for CTL. Our results show that: 1) In addition to acquisition of cell surface molecules, including MHC class I/peptide complexes, from pAPC, Th cells can acquire and present MHC class I-binding peptides through TCR-MHC class II interactions with pAPC; 2) the acquired Ag can be functionally presented to CTL; and 3) Ag presentation by Th cells induces naive CTL to proliferate and preferentially differentiate into cells that phenotypically and functionally resemble central memory T cells. These findings suggest a novel role of Th cells as pAPC for the development of memory immune responses.     

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.     

Regulation of apoptosis and replicative senescence in CD8+ T cells from patients with viral infections

Activated T lymphocytes are generated during an immune response. The induction of T lymphocyte proliferation is one way in which cell numbers can be controlled. However, once generated, the increased numbers of cells must be removed in order to re-establish cellular homoeostasis within the immune system. In this paper we describe how the numbers of activated T cells can be regulated by two distinct mechanisms, namely apoptosis and replicative senescence. In addition, we suggest that the regulation of cell clearance, as opposed to cell persistence, after an immune response is intimately involved in the generation of immune memory.