Showing papers in "Annual Review of Immunology in 1989"

TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties.

Abstract: Effector functions in the immune system are carried out by a variety of cell types, and as our understanding of the complexity of the system expands, the number of recognized subdivisions of cell types also continues to increase. B lymphocytes, producing antibody, were initially distinguished from T lymphocytes, which provide help for B cells (1, 2). The T-cell population was further divided when surface markers allowed separation of helper cells from cytotoxic cells (3). Although there were persistent reports of heterogeneity in the helper T-cell compartment (reviewed below), only relatively recently were distinct types of helper cells resolved. In this review we describe the differences between two types of cloned helper T cells, defined primarily by differences in the pattern of lymphokines ynthesized, and we also discuss the different functions of the two types of cells and their lymphokines. Patterns of lymphokine synthesis are convenient and explicit markers to describe T-cell subclass differences, and evidence increases that many of the functions of helper T cells are predicted by the functions of the lymphokines that they synthesize after activation by antigen and presenting cells. The separation of many mouse helper T-cell clones into these two distinct types is now well established, but their origin in normal T-cell populations is still not clear. Further divisions of helper T cells may have to be recognized before a complete picture of helper T-cell function can be obtained.

The biology of cachectin/TNF--a primary mediator of the host response

Abstract: Inflammation, the most ancient aspect of the host immune response, is surely of great value to the host, insofar as agents that suppress inflam­ mation in a nonspecific fashion predispose to infection. Yet, the inflam­ matory response to invasive organisms may also, if sufficiently intense or inappropriately prolonged, cause injury or death. A delicate balance has thus been achieved, one which clinicians strive to maintain through judicious application of anti-inflammatory medications (e.g. glucocorti­ coids, nonsteroidal anti-inflammatory agents, and cytotoxic drugs). Only recently have we come to understand that many aspects of this primitive response to host invasion are governed by polypeptide hormones, in turn produced by immune effector cells. Moreover, we have come to appreciate the pleiotropic properties of these so-called "cytokines." It would appear that a ' limited number of cytokines are capable of orches­ trating disease states that scarcely resemble one another; among them, endotoxic shock, graft-vs-host disease, cerebral malaria, and cancer cachexia. Cells of monocyte/macrophage lineage play a central role in cytokine ("mono kine") production and so act to modulate many aspects of the inflammatory response. While devoid of specificity and immunologic mem-

Clonal Expansion Versus Functional Clonal Inactivation: A Costimulatory Signalling Pathway Determines the Outcome of T Cell Antigen Receptor Occupancy

Abstract: Etude du controle de la proliferation des lymphocytes T par les cellules presentant l'antigene. Examen des signaux biologiques et biochimiques impliques dans ce mecanisme. Proposition d'un modele permettant d'expliquer les phenomenes

Antigen Recognition by Class I-Restricted T Lymphocytes

Abstract: The work discussed here offers a unified view of T-cell recognition and suggests that class-I and class-II molecules have a closely related function in the presentation of peptides to T lymphocytes. The epitopes recognized by class I-restricted T cells that have been defined with peptides in the 4-6 hr lysis assay have all been derived from endogenously synthesized proteins expressed by virus infected or transfected cells. Evidence is accumulating that a cytoplasmic degradation system may be involved in the generation of these epitopes. The analysis of the specificity of CTL responses with synthetic peptides has demonstrated the control of immune responses to isolated epitopes by class-I genes and the great diversity of the receptor repertoire for individual class-I-restricted epitopes.

The leukocyte common antigen family.

Abstract: The leukocyte-common antigen (L-CA) family is a group of high molecular weight glycoproteins uniquely expressed on the surface of all leukocytes and their hemopoietic progenitors ( 114). Members of this family differ by both protein sequence and carbohydrate structures and are expressed by leukocyte populations in specific patterns ( 15-27). An example of the differential expression is shown for the rat L-CA family in Figure 1 ( 19). Thymocytes express the lowest apparent molecular weight form of 1 80 kd; B lymphocytes express the highest form, 220 kd; and T lymphocytes express multiple forms. Differences also exist between T-cell subsets (Figure 1 C); CD8 T cells (Te/s) express the higher molecular weight forms more abundantly than do CD4 T cells (T H) ' The cell-type-specific patterns of expression are conserved throughout mammalian evolution ( 1, 2, 91 1, 19, 28), and there appear to be similar patterns of expression in chicken lymphocytes (29). L-CA is referred to in the literature by different names, including T200 (30), B220 for the B cell form ( 1 2) , the mouse allotypic marker Ly-5 ( 3 1 ) and more recently CD45 (32). L-CA is the most accurate descriptive name and is used for the purpose of this review. The L-CA family is a major cell surface component of lymphocytes and carries much of the carbohydrate of these cells. It has been estimated that 10% of the lymphocyte surface is occupied by one or more L-CA members (33). Because of this abundance, L-CA was easily detected on SDS-poly­ acrylamide gels of lymphocyte membranes (36-39) (Figure lA). It was also initially characterized as the major specificity of antilymphocyte sera (34) and as an allotypic marker (31 , 35). The primary protein structure has been determined from the analysis of cDNA clones, and this information,

Heterogeneity of Mast Cells and Phenotypic Change Between Subpopulations

Abstract: Mast cells are not seen in routine histological sections stained with hema­ toxilin and eosin, but a considerable number of mast cells are found in various tissues that are properly fixed and stained with dyes such as toluidine blue and Alcian blue. The substances in granules that stain specifically with these dyes are proteoglycans, which are negatively charged and thought to form complexes with positively charged proteases and histamine. Mast cells have high affinity IgE receptors on their surface, and the immunological activity of mast cells is mediated through these IgE recep­ tors (1). Binding of antigens to IgE molecules results in the formation of linkages between IgE receptors, and then the release of the granules themselves or chemical mediators in the granules (2). This process con­ stitutes an important step in the immediate hypersensitivity reaction that occurs in allergic diseases such as urticaria, bronchial asthma, and allergic rhinitis. In addition to having a role in allergic diseases, mast cells have a physiological role as an effector of host defense mechanisms in intestinal helminth infection (3-5) and dermal tick infestation (6, 7). Although some of cytochemical and functional characteristics of mast cells are common also to basophils, these two types of cells can be dis­ tinguished with an electron microscope (8). Moreover, their differentiation

Probing the human B-cell repertoire with EBV: polyreactive antibodies and CD5+ B lymphocytes.

Abstract: Presentation de l'utilisation du virus Epstein Barr (EBV) comme outil d'investigation du repertoire des lymphocytes B humains. Etude de la production d'anticorps et identification de la sous-population lymphocytaire B CD5+ impliquee dans la production d'anticorps polyreactifs. Etude du repertoire des lymphocytes B dans le cas de maladies autoimmunes

Cell biology of cytotoxic and helper T cell functions: immunofluorescence microscopic studies of single cells and cell couples.

Abstract: This review deals with certain important features of the cell biology of natural killer (NK) cells, cytotoxic T lymphocytes (CTL), and helper T (Th) cells. These features appeared originally in studies of the cell biology of cells other than immunological cells, and their relevance to immune cell interactions was then appreciated and explored. This brief review is therefore meant to be selective rather than exhaustive, and it focuses primarily on problems that have been intensively studied in our laboratory over the past decade. At the outset, it should be emphasized that we concentrate on investigations of single (generally cloned) T cells and cell couples, rather than of cell populations. Recent reviews have appeared that deal with other aspects of the cell biology of T cells and their interactions (1-7). The entree to this work stemmed from our investigations of eukaryotic cell motility; these have been separately reviewed (8). These studies are considered briefly first, since they not only introduce the ideas that have played a prominent part in our immunological work, but they also demon-

Cells and Molecules that Regulate B Lymphopoiesis in Bone Marrow

Abstract: Mature and immature forms of eight different types of blood cells are tightly packed within the spaces of bone marrow, complicating inves­ tigation of how it is efficiently regulated. Hundreds of billions of cells of the various lineages are produced daily in this vital organ and exported to other tissues via processes which are responsive to inflammation and other systemic events. Because of advances in cell separation and culture techniques, rapid progress is now being made in resolving steps in each differentiation pathway. It is even more interesting that regulatory inter­ actions between cells are being appreciated and defined in molecular terms. This review focuses on cells of the humoral immune system and those steps involved in their formation that can be observed and manipulated in culture. Purified recombinant molecules can now be used to elicit particular responses in cultured lymphocyte precursors, and the probable source of such regulatory substances is becoming clearer. Moreover, cells that comprise the inductive microenvironment of bone marrow are themselves subject to exquisite regulation. In some cases, this occurs via factors they can themselves make, i.e. autocrine regulation. Information of this kind is relevant to the treatment of a number of diseases. However, while cell culture models have made it possible to identify many molecules that affect proliferation and differentiation of B-cell precursors, they do not provide a completely accurate representation of intact bone marrow. For example, there are indications that compensatory circuits and "quality control"

The immune system of xenopus

Abstract: Presentation des elements du systeme immunitaire de Xenopus: systeme lymphoide, systeme d'histocompatibilite majeur, immunoglobuline. Le fonctionnement de ce systeme est considere (reponse immune, tolerance, diversite des anticorps) ainsi que son developpement. L'impact de la polyploidie sur le systeme immunitaire de Xenopus est discute

Stable expression and somatic hypermutation of antibody V regions in B-cell developmental pathways

Abstract: Etude des differentes voie de differenciation des cellules B grâce a l'etude du rearrangement des genes des regions variables

Microanatomy of Lymphoid Tissue During Humoral Immune Responses: Structure Function Relationships

Abstract: The complex cellular interactions involved in the regulation of immune responses have generally been studied in vitro. An implicit assumption is that cells perform the same roles in culture as they do in vivo. However, it should be appreciated that secondary lymphoid tissues are highly organ­ ized and that this functional architecture is destroyed in the process of suspending cells. The aim of this review is to relate novel structures observed in the lymphoid nodule or follicle with induction of the secondary antibody (A b) response. Special attention is focused on antigen (Ag) recog­ nition, Ag processing, and Ag presentation steps that appear to occur in the lymphoid nodule. In contrast with the primary response, Ab is present when the booster immunization is given. This Ab binds the immunogen, and immune complexes are rapidly formed. These immune complexes localize in lymphoid nodules in minutes, germinal centers develop rapidly, and Ab production and memory B-cell production are accelerated. These

Manipulation of T-Cell Responses with Monoclonal Antibodies

Abstract: Presentation de l'immunotherapie par utilisation d'anticorps monoclonaux chez des modeles animaux. Etude de l'impact de ces etudes sur les transplantations. Reflexion sur l'utilite des anticorps monoclonaux dans l'etablissement d'une tolerance immunologique

The Cellular Basis of T-Cell Memory

Abstract: One of the major characteristics of the immune system is its ability to react more quickly and more intensely on the second exposure to an antigen. This characteristic, usually referred to as immunologic memory, was first observed in studies of antibody production in vivo (reviewed in 1). The secondary, or anamnestic, response to an antigen not only results in the production of increased levels of antibodies, but these antibodies also generally have a higher affinity for antigen compared to those antibodies produced during the primary response (2). Memory at the B-cell level is generally accepted as the result of selection and specific expansion of clones secreting high affinity antibody molecules (3, 4). Molecular studies suggest that somatic hypermutation of antibody variable-region genes during the primary response may be responsible for the occurrence of B cells express­ ing high affinity receptors (reviewed in 5). However, the differentiation pathway involved in the generation of memory B cells is still poorly understood. In particular, it is not clear how, in the primary response, some of the B cells differentiate into terminal plasma cells and others into memory cells. While there is ample evidence that immunologic memory also involves T cells, our understanding of the molecular and cellular basis of T-cell secondary responses is quite limited. Following early studies dem­ onstrating that cytolytic T lymphocytes (CTL) are not necessarily terminal cells but may differentiate, at least in vitro, into cells exhibiting the expected properties of memory cells (6), attempts have been made to define quan­ titative and qualitative differences between memory T cells and T cells that have not yet been stimulated by antigen (which are often designated as

T Cell Receptors in Murine Autoimmune Diseases

Abstract: Presentation d'un modele de maladie autoimmune dans laquelle sont impliques les lymphocytes T, l'encephalomyelite murine. Etude du role des anticorps diriges contre le recepteur des lymphocytes T dans le traitement des maladies auto-immunes. Le role des lymphocytes T CD4 + est plus particulierement envisage

T-cell responses and immunity to experimental infection with leishmania major.

Abstract: Leishmaniases are infectious diseases 9f protozoan origin that represent an increasing public health problem worldwide (1). There are indications that these diseases also affect an increasing number of immuno­ compromised patients in some areas of developed countries (2). The organisms responsible for these diseases are trypanosoma tid protozoans of the genus Leishmania. The parasites are transmitted to their mammalian hosts by the bite of an infected phlebotomine sandfly. The life cycle of all species of Leishmania includes two developmentally and morphologically distinct forms: (a) the extracellular, flagellated promastigotes which col­ onize the digestive tract of the insect vector, and (b) the sessile amastigotes which are found exclusively as obligate intracellular parasites within cells of the mammalian reticuloendothelial system (3). Infection of humans with Leishmania results in a broad spectrum of disease profiles whose features depend upon the characteristics of the different Leishmania species and the efficiency of the host's immunological response to the parasite (4). That natural self-healing infection leads to the development of immunity to reinfection strongly suggests that control of leishmaniasis by prophylactic immunizaton is possible. Since the entire spectrum of clinical manifestations seen in humans

Molecular Genetics of Chronic Granulomatous Disease

Abstract: Chronic granulomatous disease is an inherited disorder characterized by the failure of phagocytic cells to produce superoxide upon the ingestion of microorganisms due to a lesion in a membrane-associated NADPH-oxidase. The components of the oxidase have been incompletely characterized by standard biochemical approaches. A genetic strategy has recently led to the identification of the gene affected in the common X-linked form of CGD without reference to its protein product. The X-CGD gene, assigned to chromosome position Xp21.1, encodes a phagocyte-specific RNA transcript that is mutated in patients with X-CGD. Antisera directed toward the predicted protein product of the X-CGD gene recognize a 90 kD membrane glycoprotein, which corresponds to the larger subunit of the phagocyte b-cytochrome heterodimer. The recent genetic and biochemical findings provide an explanation for the consistent absence of the b-cytochrome spectrum in X-CGD, and establish this cytochrome as an essential component of the phagocyte oxidase. The primary amino acid sequence of both the 90 kD b-cytochrome subunit and the 22 kD subunit (cloned as the cDNA using a specific antisera) have no significant similarity to other proteins, including previously studied cytochromes. As both subunits of the b-cytochrome heterodimer are absent in X-CGD, despite a genetic deficiency of only the larger polypeptide, a close interaction between the two subunits may be important for b-cytochrome stability and function. Expression of the b-cytochrome large subunit mRNA is increased by interferon-gamma, an important macrophage activator. Partial or complete restoration of oxidase activity in some X-CGD patients treated with interferon-gamma suggests new therapeutic approaches in the management of this disorder. Molecular reagents prepared from the cloned X-CGD cDNA or gene may prove to be clinically useful in prenatal diagnosis and may provide a basis for somatic gene therapy in future.

T-Cell Recognition of Minor Lymphocyte Stimulating (MLS) Gene Products

Abstract: The immune system has evolved with a highly diverse antigen-specific repertoire capable of recognizing an extraordinarily large universe of foreign antigens. As a corollary of this wide diversity, the precursor fre­ quency of T cells specific for any given foreign antigen is generally very low, so low, in fact, that proliferative responses of naive T-cell populations to these antigens are undetectable. However, prominent exceptions to this generalization have been identified. In multiple species, cell surface alloan­ tigens encoded by genes of the major histocompatibility complex (MHC) are recognized by T cells at a high precursor frequency and are capable of eliciting a strong proliferative mixed lymphocyte response by unprimed T­ cell populations ( 1 , 2). In the mouse, a second set of determinants, the minor lymphocyte stimulatory (Mis) determinants, also induce strong proliferative responses by naive T cells (3-5). The finding that T cells are reactive to MHC and to Mis determinants at extraordinarily high pre­ cursor frequencies (1 , 2, 6, 7) has generated interest in understanding the biologic significance of these two systems. A great deal of information has been accumulated concerning the structure and function of MHC genes and their products, and the biologic importance of MHC-encoded deter­ minants has been extensively documented (reviewed in 8). In contrast, although MIs gene products were described as lymphocyte

V-region connectivity in t cell repertoires

Abstract: Article de synthese presentant la connectivite entre les recepteurs des cellules T. Mise en evidence d'une interaction entre les recepteurs des lymphocytes T et les idiotypes des immunoglobulines. Role de cette interaction dans la selection et la maintenance du repertoire immunologique des cellules T