Immunological memory to an autoantigen: the in vitro response to thyroglobulin.
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Memory B and T cells.
Three remarkable and unique features of the immune system are specificity, diversity, and memory. Immunological memory involves both T and B cells and results in a secondary antibody response that is faster, of higher affinity, and results in the secretion of non-IgM isotypes of Ig. In this review we discuss the properties of memory T and B cells, their specific receptors, and the events which occur both in the nucleus and on the cell surface during generation and activation of these cells. Although memory T and B cells use different mechanisms to elaborate memory, there are a number of interesting analogies: lymphokines vs antibodies and affinity maturation of B cell antigen receptors vs upregulation of adhesion molecules on T cells. Finally, we discuss the importance of these cells in health and disease and suggest what impact additional information about these cells might have on the manipulation of the immune response.
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Aspects of cytotoxic T cell memory.
Immunological T cell memory manifest itself in an accelerated second-set graft, or allogeneic tumour cell, rejection. Memory viral-immune cytotoxic T cells have shortened kinetics of induction in vivo and differentiate into more potent effector cells in vitro. The requirements for induction of memory T cells are less stringent than for naive T cells. Memory T cells can be activated by antigen (signal 1) or interaction with co-stimulatory molecules (CD28/CD80, signal 2) alone. Memory T cells are phenotypically distinguishable from naive T cells by a number of cell surface markers, but not from activated T cells. Persistence of antigen is not required for the maintenance of long-lived memory. Continuous stimulation by signal 2 alone and or longevity is sufficient to explain life-long persistence of T cell memory. All available data on memory T cells are consistent with a deterministic model of T cell memory formation, following a precise pathway of T cell differentiation.
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Interleukin 7 and T cell receptor signals regulate homeostasis of CD4 memory cells.
Immunological memory depends on the long-term maintenance of memory T cells. Although the factors that maintain CD8 T cell memory are well understood, those responsible for CD4 memory are not well defined. We have shown here that interleukin 7 (IL-7) was an important survival factor for CD4 memory T cells that together with T cell receptor (TCR) signals regulated homeostasis of the CD4 memory population in lymphopenic conditions and in the intact immune system. Thus, IL-7 contributes to the maintenance of all naive and memory T cell subsets, and therefore controls the overall size of the T cell pool.
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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.
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Modelling T-cell memory by genetic marking of memory T cells in vivo.
Immunological memory is the ability of the immune system to respond with enhanced vigour to pathogens that have been encountered in the past. Following infection or immunization, most effector T cells undergo apoptotic cell death, but a small fraction of these cells, proportional to the early antigen load and initial clonal burst size, persist in the host as a stable pool of memory T cells. The existence of immunological memory has been recognized for over 2,000 years, but our understanding of this phenomenon is limited, primarily because memory lymphocytes cannot be unequivocally identified as they lack specific, permanent markers. Here we have developed a transgenic mouse model system whereby memory T cells and their precursors can be irreversibly marked with a reporter gene and thus can be unambiguously identified. Adoptive transfer of marked CD8+ T cells specific for lymphocytic choriomeningitis virus protected naive recipients following viral challenge, demonstrating that we have marked memory T cells. We also show that cytotoxic effector lymphocytes that develop into memory T cells can be identified in the primary response.
Adoptive Transfer↗
Fratricide: a mechanism for T memory-cell homeostasis.
Immunological memory depends on a self-renewing pool of antigen-specific T memory (Tm) cells but the homeostatic mechanisms that maintain the size and diversity of the pool are largely unknown. Competition for space or growth factors has been suggested as a mechanism but how these factors themselves are regulated is unclear. We suggest that Tm-cell fratricide by Fas-mediated apoptosis results in a density-dependent death rate that controls the size of the pool without requiring competition for resources or an external quorum-sensing mechanism. A mathematical model based on this concept predicts the known behaviour of the Tm pool, including observed differences in heterogeneity of the CD4 and CD8 compartments and might provide a paradigm for homeostasis of other haematopoietic-cell populations.
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Memory T lymphocytes.
Immunological memory protects organisms from recurrent challenge by pathogens. The persistence of a heightened reactive state initiated by antigenic challenge is mediated by long-lived memory lymphocytes. The survival of memory T cells is thought to require stimulation through the T cell receptor (TCR), sometimes by persistent antigen. However, memory T cells can survive in the absence of antigen, in which case TCR stimulation provided by cell surface self-peptide/ major histocompatibility complex (MHC) molecules and cytokines are required to sustain memory T cells. Recent work using mouse models has provided insights into the origin of memory T cells. Understanding the mechanisms that underlie the differentiation and persistence of memory T cells may improve the effectiveness of vaccines through the induction of T cell memory.
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Protection against immunopathological consequences of a viral infection by activated but not resting cytotoxic T cells: T cell memory without "memory T cells"?
Immunological memory is a key characteristic of specific immune responses. Persistence of increased levels of precursor T cells is antigen-independent and is often used as an indicator of T cell memory. This study documents that, depending on the chosen readout, cytotoxic T lymphocyte (CTL) memory against lymphocytic choriomeningitis virus (LCMV) appears long- or short-lived in the absence of persisting antigen. To study T cell memory in the absence of persisting antigen, either short-lived antigens were used for immunization or adoptive transfer methods were used to eliminate possibly persisting antigen. These experiments revealed that increased specific precursor frequencies and CTL-mediated protection against an i.v. infection with LCMV were long-lived. In contrast, CTL-mediated protection against a peripheral infection of the skin with LCMV, or of the ovary with recombinant vaccinia virus, was short-lived. These results show that maintenance of increased specific CTL precursor frequencies and central T cell memory in lymphoid tissue (where preexisting neutralizing antibodies usually provide protection anyway) is long-lived and antigen-independent. In contrast, in protection against peripheral viral infections, where the relative kinetics of virus growth and virus elimination by T cells are of key importance, T cell memory is short-lived in the absence of antigen. This indicates that peripheral T cell memory in antibody-inaccessible tissues is mediated by antigen-activated effector T cells and apparently not by specialized memory T cells.
Adoptive Transfer↗
T-cell memory: new perspectives.
Immunological memory provides excellent protection against a wide variety of different pathogens. Compared to the primary encounter with antigen, the secondary response is more rapid and effective. So much so, that reexposure often goes unnoticed by the host. The specific nature of memory implies that it is especially dependent on T and B cells, the cells of the immune system which recognize antigen; it follows that the changes which occur in these cells during priming must account in large part for the memory response. Here, we will summarize what is and what is not known about memory in the CD4 T-cell population.
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Regulation of development and function of memory CD4 subsets.
Immunologic memory refers to the dramatic response to previously encountered antigen (Ag) that is largely controlled by CD4 T cells. Understanding how CD4 memory is regulated is essential for exploiting the immune system to protect against disease and to dampen immunopathology in allergic responses and autoimmunity. Using defined adoptive-transfer models, we are studying parameters that affect differentiation of memory CD4 cells in vivo and have found that a complex interplay of T cell receptor signaling, costimulation, and cytokines can determine the extent of memory development and the balance of Th1 and Th2 memory subsets. On challenge, memory CD4 cells localize in sites of Ag exposure and develop into effectors that regulate memory responses. We are investigating the roles of adhesion molecules, cytokines, and chemokines in the selective recruitment of CD4 memory subsets to address mechanisms by which memory T cells provide long-lasting immunity and, in our recent studies, to determine how memory CD4 cells contribute to the development of autoimmune diabetes.
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Genetic control of the immune response. A selective defect in immunologic (IgG) memory in nonresponder mice.
The kinetics of antibody formation after immunization with the synthetic polypeptide poly-L(Tyr, Glu)-poly-D, L-Ala--poly-L-Lys [(T, G)-A--L] in aqueous solution were studied in genetically high (H-2(b)) and low (H-2(k)) responder strains of mice. During the 1st wk after immunization both strains developed brisk primary responses consisting of IgM antibody. With subsequent antigen challenge, only the high responder mice showed immunological memory, producing high titers of IgG antibody. In contrast, the low responder mice continued to make a persistent low level of IgM antibody and appeared unreactive to secondary or tertiary antigen challenge. These data are consistent with the hypothesis that the immune response-1 gene [controlling response to (T, G)-A--L] exerts its effect on the immune response at the time of switchover from IgM to IgG antibody production.
Amino Acid Sequence↗
Recombinant idiotypic TCRbeta chain immunization in mice generates antigen specific T cell response.
Vaccination remains the most cost-effective means of preventing infectious diseases. Success of vaccination depends on generation of effective memory response. Understanding the mechanism of generation and maintenance of immunological memory would help in the design of rational vaccines. T lymphocytes play a central role in the generation of protective immune response against many microbial infections. 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 a model antigen, chicken ovalbumin specific T cell receptor beta chain (idiotypic TCR) generates TCR specific antibody and anti-idiotypic T cell responses as well as ovalbumin specific T cell response. We further show that boosting of ovalbumin primed mice with ovalbumin specific idiotypic TCRbeta DNA or TCRbeta protein gives memory response for ovalbumin. This study provides experimental evidence for perpetuation of immunological memory through idiotypic network interactions.
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T cell memory: heterogeneity and mechanisms.
Immunological memory is manifested by the body's ability to enjoy long-term protection against specific pathogens previously encountered through illness or vaccination. This memory response resides in the long-lived, previously activated memory T and B lymphocytes that are believed to exist in a quiescent state. Recent advances in studies on T cell memory have revealed heterogeneity in the T cells that mediate memory responses that may have implications for the generation and maintenance of these cells over time. This review will present these recent findings on memory T cells in the context of past research and current models for the generation and persistence of memory T cells.
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One-dose immunization against paralytic poliomyelitis using a noninfectious vaccine.
Recent advances in production and standardization of noninfectious poliovirus vaccine now make it feasible to induce durable immunity against paralytic poliomyelitis with one dose of a suitably standardized vaccine. A single dose of a vaccine containing 40, 8, and 32 D-antigen units of type 1, 2, and 3, respectively, administered to six-month-old infants, was observed to induce antibody levels of greater than or equal to 1:4 in greater than 90% and immunologic memory in all. Since protection against paralysis is associated with the presence of either type-specific serum antibody or type-specific immunologic memory, and since immunologic memory once induced is irreversible, then lifelong immunity to paralytic poliomyelitis can be induced with a single dose of a suitably standardized vaccine administered at five to seven months of age. In areas of the world where exposure to poliovirus can occur before this age, vaccine should be administered earlier. Until the influence of age and/or maternal antibody has been further studied, infants immunized before the age of six months should receive a second dose after six months of age.
Antibodies, Viral↗
Mucosal effector memory T cells: the other side of the coin.
Immunological memory allows for rapid and effective protective immunity to previously encountered pathogens. New insights in understanding specific memory differentiation and function have now indicated that in addition to providing enhanced immunity, an important purpose of immunological memory is to provide immediate protection at all sites of the body, including non-lymphoid tissues. Effector memory CD8 T cells have the capacity to reside long-term at epithelial surfaces, where they allow for rapid containment of the invading pathogens at the local entry site and prevent systemic spreading and excessive immune responses. The accumulation of tissue-specific memory T cell subsets, together with cross-reactivity of these antigen-experienced T cells even to unrelated pathogens, provides flexibility and expansion of their specificity repertoire that over time greatly surpasses that of the declining naïve T cell populations. This review will discuss new insights into T cell memory. We will focus in particular on the generation and function of effector memory CD8 T cells at the intestinal mucosa, which represents one of the largest entry sites for pathogens.
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Booster immunization of antigen primed mice with anti-idiotypic T cells generates antigen-specific memory T cell response.
Immunological memory is characterized by quick and enhanced immune response after re-exposure to the same antigen. In the present work, we have shown that anti-idiotypic T cells are generated in mice after immunization with idiotypic T cell clone or polyclonal T cell specific for nucleocapsid protein of Rinderpest virus. Further, we have shown that N specific idiotypic T cell receptors from apoptotic idiotypic T cells are processed by bone marrow derived dendritic cells and presented to cognate anti-idiotypic T cells. Evidence has been provided for the existence of antigen specific T cell idiotypic network in the body. Boosting with antigen specific anti-idiotypic T cells generates memory response in the antigen-primed mice.
Adoptive Transfer↗
T-cell memory: the connection between function, phenotype and migration pathways.
Immunological memory is a fundamental feature of vertebrate immune systems, providing enhanced protection against previously encountered antigens. The established view has been that immunological memory results from clonal expansion and long-term survival of specialized memory cells. Recently, the nature of memory T cells has come under closer scrutiny because of the ability to distinguish naive and memory T cells phenotypically, particularly in humans. In this article, Charles Mackay discusses three features of memory T cells that help to explain the nature and function of these cells: the increased expression of adhesion and activation molecules on memory T cells, their potent functional status and their specific pathways of recirculation.
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