Chapter 4 Vol. II: Adaptive Immunity

Adaptive immunity Introduction The immune response is dynamic and dependent on diverse intercellular interactions, the tissues and cells that produce the host response are scattered throughout the body and are highly motile, and many lymphocytes can morph from one functional state to another during their lifetimes It is the adaptive response that executes the highly specific assault on virus particles and infected cells, discriminating not only infected from uninfected cells, or one virus type from another, but also between two viruses of the same family that may differ by a single amino acid Attributes of the host response Speed The interval between viral infection and immune-mediated resolution defines the window during which disease may occur The virus reproduction rate, yield, and distribution in the host are pitted against the efficient of detection and clearance by host defenses While the antiviral actions of intrinsic and innate immunity usually keep the virus in check during the critical early days following infection, the subsequent massive clonal expansion of antigen-specific T and B cells is often what deals the fatal blow to a virus infection These "immunological meeting places" are the sites at which antigen-presenting cells, transported in the lymph, encounter na ve lymphocytes that circulate in the blood Diversity and specificity Most of an individuals na ve cells will never encounter their cognate antigen, and consequently they call not be activated and their numbers will not increase T and B cells possess surface receptors that recognize small portions of a viral protein (or three-dimensional facets of a protein) termed epitopes The abundance and diversity of the immune repertoire may explain why otherwise healthy individuals respond differently to an encounter with the same pathogen Memory Once T and B cells have become activated by interaction with a cognate antigen, a small number are retained as memory cells, equivalent to an idling car stopped at a red light While the initial conversion of na ve to activated cells requires multiple steps and a few days, the amplification of memory cells begins almost immediately Self-control Mounting an immune defense results in the production of large quantities of cytokines and expansion of immune cells that can make the host quite ill: most of the unpleasant symptoms of infections result from the host response rather than from the virus itself Processes that an intrinsic to activated lymphocytes ensure their demise within a short period after activation: the life of an activated immune cell is exciting, but brief Lymphocyte Development, diversity, and activation The hematopoietic stem cell lineage All cells in the blood are derived from a common lineage, originating with a multi potential hematopoietic stem cell that differentiates into two discrete progenitor populations, the common myeloid stem cell and the common lymphoid stem cell Lymphocyte differentiation is marked by an orchestrated loss of stem cell-specific proteins and a concomitant acquisition of those that are characteristic of fully differentiated leukocytes ,Multipotential hematopoietic stem cell Common myeloid progenitor Erythrocyte Common lymphoid progenitor Mast Cell Myeloblast Natural killer cell (Large granular lymphocyte) Small lymphocyte Megakaryocyte Basophil Neutrophil Eosinophil Monocyte T lymphocyte B lymphocyte Thrombocytes Plasma cell Macrophage The two arms of adaptive immunity The adaptive response comprises two complementary actions, the humoral response (B cells and the antibodies they produce) and the cell-mediated response (helper and effector T cells) In general, antibodies bind and inactivate virus particles in the bloodstream and at mucosal surfaces, whereas T cells recognize and kill infected cells, the source of new virus particles The major effectors of the adaptive response: B and T cells B cells As each B cell matures, it synthesizes a unique antigen receptor, the B-cell receptor, which is a membrane-bound antibody The daughter cells produced by each division differentiate into effector plasma cells and a small number of memory B cells The B cell, like dendritic cells, is also an antigen-presenting cell that uses the major histocompatibility complex (MHC) class II system and exogenous antigen processing T cells T-cell precursors are also produced in the bone marrow, but in contrast to B cells, which complete their maturation in this compartment, a T-cell precursor must migrate to the thymus gland to mature; hence the "T" in T cell Unlike B-cell receptors, which can bind to epitopes displayed on components of extracellular pathogens, the T-cell receptor binds only to pathogen-derived peptides, called epitopes, presented in the context of MHC molecules on the surface of antigen-presenting cells, or infected cells As with the activation of na ve B cells, when the T-cell receptor engages an MHC molecule carrying the appropriate peptide, a signal transduction cascade is initiated that leads to transcription of specific genes Lymphocytes can be distinguished by the presence and profile of specific cell surface proteins called cluster-of-differentiation (CD) markers Once in the thymus, they differentiate sequentially, initially producing both CD4 and CD8 proteins ("double-positive") and then either CD8 and CD4 ( single-positive ) CD8+ cytotoxic T lymphocytes Cells that possess the CD8 molecule on their cell surface are called CD8+ T cells, and are also referred to as cytotoxic T lymphocytes (CTLs) When an activated CTL "finds" a target cell displaying the cognate epitope, it can destroy that cell In addition to their cell-killing activity, CTLs are also major producers of interferon-gamma and tumor necrosis factor alpha, both of which aid in recruitment of other immune cells and directly interact with the infected cell to induce an antiviral program CD4+ T-cell populations After binding to a class II MHC molecule on B cells or professional antigenpresenting cells that presents the cognate peptide, the naive CD4+ Th cell becomes activated and matures into one of four types of CD4+ T cell Diverse receptors impart antigen specificity to B and T cells Highly specific recognition of viral epitopes is mediated by membrane-bound antibodies on B cells and by the T-cell receptors on T lymphocytes The B-cell receptor engages discrete epitopes in intact proteins The T-cell receptor binds short, linear peptides derived from proteolytically processed proteins, presented on the infected cell surface by class I MHC proteins The binding to an antigenic peptide has profound effects on the T or B lymphocyte bearing that receptor: the lymphocyte may respond by producing cytokines, entering a period of rapid cell division, killing the cell that bears the foreign protein or peptide, or synthesizing antibodies At its completion, each transmembrane cell surface receptor possesses a constant (C) region that transduces critical signals following antigen engagement and a variable (V) region that binds to a peptide (for T cells) and or other structural feature (B cells) This process [recombination] occurs independently for both the heavy and Variable light chains, and hence the pairing of a region unique heavy chain with a unique light Light chain further contributes to receptor chains diversity A large number of enzymes that . mediate DNA cleavage, nucleotide additions, and ligation participate in Heavy Constant this process, including the recombinasechains region activating genes (RAGs) Two concurrent quality control processes, negative selection and positive selection, weed out T and B cells with dysfunctional receptors Events at the site of infection set the stage for the adaptive response Acquisition of viral proteins by professional antigen-presenting cells enables production of pro-inflammatory cytokines and establishment of inflammation A consequence of local innate defense is that tissue-resident myeloid cells, such as macrophages or dendritic cells, engulf remnants of dying cells and virus particles, a process called phagocytosis When a dendritic cell ingests a virus particle or a portion of a dying cell that contains the virus, this material becomes trapped in an intracellular phagosome, which then fuses with a lysosome The inflammasome and cytokine release Important checkpoints that require multiple, independent switches to be engaged to result in a "go" signal help to guard against faulty or premature induction of these powerful pathways When a pathogen-associated molecular pattern is engaged by a toll-like receptor, A signal transduction cascade in these cells results in activation of NF-kB and synthesis of inflammasome components and two precursor cytokine molecules, pro-IL-1B and pro-IL-18 Inflammation The rapid local release of cytokines at the site of infection by activated antigenpresenting cells produces physiological changes that are characterized as inflammation Moreover, the binding of TNF-alpha to its receptor on infected cells initiates a signal transduction cascade that activates cellular caspases, resulting in their death via apoptosis The four classical signs of inflammation are redness, heat, swelling, and pain. Such symptoms result from increased blood flow and capillary permeability, influx of phagocytic cells, and local tissue damage Local inflammation causes blood vessels to constrict, resulting in swelling of the capillary network and leading to redness (erythema) and an increase in local tissue temperature, primarily due to IL-1 production In general, noncytopathic viruses do not induce a strong inflammatory response, in great part because the absence of cellular debris from dying cells cannot promote a host response Activated antigen-presenting cells leave the site of infection and migrate to lymph nodes Activation and maturation of tissue-resident dendritic cells at the site of infection causes them to migrate to lymphoid tissues, which include the extensive network of lymph nodes strategically located throughout the body, near common routes of pathogen exposure Although all lymph nodes are meeting places for activated antigen-presenting cells and na ve lymphocytes, there are some interesting features that distinguish nodes based on their proximity to portals of pathogen entry M cells (microfold or membranous epithelial cell) have membrane invaginations (pockets) that harbor immature dendritic cells, B and CD4+ T lymphocytes, and macrophages In particular, Langerhans cells, the predominant professional antigen-presenting cells of the epidermis, serve as sentinels for early warning and reaction Virus particles at the primary site of infection can suppress responses of lymphoid cells that are associated with the mucosal and cutaneous immune systems by inducing their lysis or causing functional misregulation Thereafter, some transfer of antigen occurs between the Langerhans cell and a dendritic cell that is resident in the lymph node, a process called cross-presentation Antigen processing and presentation Professional antigen-presenting cells induce activation via costimulation Priming of na ve lymphocytes is mediated by cell surface proteins that enable costimulation: two simultaneous protein-protein interactions are required between a professional antigen-presenting cell and a na ve, quiescent lymphocyte to achieve activation This fail-safe mechanism ensures that naive T cells are not activated in error: if a naive T cell encounters an antigen-displaying cell in the absence of costimulation, anergy or tolerance may occur Presentation of antigens by class I and class II MHC proteins Antigenic peptides can be displayed on infected cells or professional antigenpresenting cells by one of two related but distinct protein assemblies: class I and class II MHC proteins MHC class I is present on the surface of almost all cells, whereas MHC class II is generally found only on the surfaces of mature dendritic cells, macrophages, and B lymphocytes In this way, the T- or B-cell receptor detects the presence of "altered self": a "self" protein (the MHC molecule) that is structurally altered by the presence of a viral protein fragment MHC class I proteins present antigens that are synthesized inside of infected cells, whereas MHC class II molecules display antigens derived from extracellular pathogens or those that have been engulfed by phagocytosis Cytotoxic T cells recognize infected cells by engaging MHC class I receptors These viral (and cellular) peptides are produced and displayed via a pathway called endogenous antigen presentation Such proteins are marked for destruction by the covalent attachment of multiple copies of the small protein ubiquity, and following ATP-dependent unfolding, they are broken down in the internal chamber of the protease Within the ER, binding of peptides to newly synthesized MHC class I proteins allows these molecules to adopt their native conformation and to be transported to the cell surface via the secretory pathway Presentation of cellular peptides is usually ignored, because autoreactive T cells were either deleted by the negative selection process during development or were not appropriately costimulated Th cells recognize professional antigen-presenting cells by engaging MHC class II receptors Mature antigen-presenting cells also carry high surface concentrations of costimulatory T-cell adhesion molecules that also bind receptors on naive Th cells in the lymphoid tissue In this process [exogenous antigen presentation], phagocytes viral particles are broken down and their proteins digested in endosomes rather than in the protease, as is the case with the endogenous pathway The CTL (cell-mediated) response CTLs lyse virus-infected cells CTLs are superbly equipped to kill virus-infected cells. Moreover, following lysis of an infected cell, they can detach and kill again Signaling from the T-cell receptor pursuant to engagement of the peptide antigenMHC complex requires clustering (aggregation) of multiple T-cell receptors and reorganization of the T-cell cytoskeleton to form a specialized structure called the immunological synapse The synapse structure contributes to stabilizing signal transduction by the T-cell receptor for the prolonged periods required for activation of gene expression CTLs kill by two primary mechanisms: transfer of cytoplasmic granules from the CTL to the target cell, and induction of apoptosis The critical contribution of CTLs to antiviral defense is demonstrated by adoptive transfer experiments in which virus-specific CTLs from an infected animal confer protection to hon immunized recipients following virus inoculation Control of infection by CTLs without killing Complete clearance of intracellular viruses by the adaptive immune system does not depend solely on the destruction of infected cells by CTLs The humoral (antibody) response Antibodies are made by plasma cells Terminal differentiation and antibody synthesis occur only if the B cell's surface antibody receptor is bound to the cognate antigen, a process that occurs chiefly within lymph nodes Binding of antigen t the B-cell receptor antibody is only part of the activation process that converts B cells into plasma cells: cytokines from Th cells are also required Types and functions of antibodies During B-cell differentiation, "switching" of the constant region of heavy-chain genes occurs by somatic recombination, a process that is regulated in part by specific cytokines, including IL-4 and IL-5, which bind to their receptors on the target B cell A subsequent challenge with the same antigen or viral infection promotes a rapid secondary antibody response with enhanced ability to recognize and bind a specific foreign antigen Virus neutralization by antibodies Antibodies contribute to antiviral defense chiefly by binding to, and causing the elimination of, free virus particles, either by initiating the complement cascade and/ or targeting bound particles for excretion Because IgA molecules must pass through such a cell en route to secretion from the apical surface, they are available during transit for interaction with viral proteins produced within the cell While some antibodies do prevent virus particles from attaching to cell receptors, the vast majority of virus-specific antibodies are likely to interfere with the concerted structural changes that are required for entry The analysis of the mutant viruses that emerge from this immunological gauntlet allows a precise molecular definition, not only of antibody-binding sites but also of parts of viral proteins important for entry Immunological memory While the primary response takes days to reach its antiviral potential, a subsequent encounter with the same pathogen awakens a massive reaction that mobilizes within hours of pathogen entry The critical differences are that memory T and B cells are more abundant and more easily activated than the rare cognate na ve cells, and that no costimulation is needed to initiate the antiviral program of the memory cells Unlike B cells, which undergo isotype switching during the primary response, in memory T cells the composition of the T-cell receptor does not change over time