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Annual Review of Immunology - Volume 12, 1994
Volume 12, 1994
- Review Articles
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The Wisdom of Hindsight
Vol. 12 (1994), pp. 1–62More LessThis essay is a highly personalized account of some of the important conceptual contributions to immunology. I have asked myself, “What were the ideas that caught my attention and how and by whom were they presented?” I have learned that most of what immunologists have called concepts deal with too small a slice of the subject. They are essentially inductive extrapolations from one experiment to a possible next step. Historically, these extrapolations extended over too narrow a chasm to account for the information available at the time. The result was that an extrapolation from one misleading observation could dominate and distort, for a significant time, the course of the field. It is also why there has been an inverse relationship between the clarity of a theory and its ease of acceptance by immunologists. Looking to the past, I have used two areas to illustrate the role of conceptualization: the self-nonself discrimination and the origin of the humoral repertoire. To illustrate all of this I have chosen as a cast & characters the founding fathers of immunologays we know it today. I hope that by taking this look into the rear view mirror our efforts will be guided in more productive ways. The take-home lesson is that we need to widen our horizon constantly to make more general concepts that then render the manipulation of the immune system more useful.
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Transepithelial Transport of Immunoglobulins
Vol. 12 (1994), pp. 63–84More LessImmunoglobulins are transported across a variety of epithelial tissues. The best studied example of this is the transport of polymeric IgA and IgM by the polymeric immunoglobulin receptor (pIgR) across many types of epithelial cells. The pIgR binds its ligand at the basolateral surface and is internalized into endosomes. Here it is sorted into vesicles that transcytose it to the apical surface. At the apical surface the pIgR is proteolytically cleaved, and the large extracellular fragment (known as secretory component) is released together with the ligand. The pIgR contains a cytoplasmic domain of 103 amino acids that contains several sorting signals. Targeting from the trans-Golgi network to the basolateral surface is determined by the membrane-proximal 17 residues of this domain. There are two endocytosis signals that contain crucial tyrosine residues. Transcytosis of the pIgR is stimulated by binding of polymeric IgA. Phosphorylation of a cytoplasmic serine promotes transcytosis of the pIgR without ligand bound. Transcytosis may be regulated by the heterotrimeric Gs protein, protein kinase C and calmodulin. IgG is transcytosed from the apical to basolateral surface in several epithelial tissues such as the placenta and the small intestine of newborn rats. The receptor for intestinal transport of IgG is structurally similar to class I MHC molecules.
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CD45: An Emerging Role as a Protein Tyrosine Phosphatase Required for Lymphocyte Activation and Development
Vol. 12 (1994), pp. 85–116More LessCD45 is one of the most abundant leukocyte cell surface glycoproteins and is expressed exclusively upon cells of the hematopoietic system. Different isoforms of CD45 are generated by alternative splicing and are expressed in cell type-specific patterns on functional subpopulations of lymphocytes. In a major advance, CD45 was identified as one of the first members of a novel class of enzymes, the protein tyrosine phosphatases (PTPs). This serendipitous discovery linked CD45 to the process of reversible protein tyrosine phosphorylation, a key regulatory mechanism for controlling the growth and division of eukaryotic cells, and provided the impetus for most of the studies described in this review. CD45 is now established as a critical component of the signal transduction machinery of lymphocytes. In particular, evidence from genetic experiments indicates that CD45 plays a pivotal role in antigen-stimulated proliferation of T lymphocytes and in thymic development. Two members of the Src-family of protein tyrosine kinases (PTKs), the p56lck and p59fyn proteins, have been implicated as physiological substrates of CD45, providing an important clue to how the action of this leukocyte-specific PTP might influence signaling by the T cell antigen receptor. Structure-function analysis of CD45 and other PTPs has identified structural features of PTP catalytic domains required for enzymatic activity. However, despite intensive efforts, little is known about how the activity of CD45 is regulated. The external domain of CD45 does not appear to be absolutely required for signal transduction by the T cell receptor, and there is currently no evidence that ligand binding modulates CD45 activity. Analysis of CD45 isoform expression has revealed a hitherto unrecognized plasticity in isoform usage by T cells and other leukocytes, adding to the regulatory complexity of isoform expression.
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Germinal Centers
Vol. 12 (1994), pp. 117–139More LessGerminal centers develop in the B cell follicles of secondary lymphoid tissues during T cell-dependent (TD) antibody responses. The B cells that give rise to germinal centers initially have to be activated outside follicles, in the T cell-rich zones in association with interdigitating cells and T cell help. After immunization with a single dose of protein-based antigen, the germinal centers formed are oligoclonal; on average three B blasts colonize each follicle. These blasts undergo massive clonal expansion and activate a site-directed hypermutation mechanism that acts on their immunoglobulin-variable (Ig-v)-region genes. Mature germinal centers are divided into dark and light zones. The proliferating blasts, centroblasts, occupy the dark zone and give rise to centrocytes that are not in cell cycle and fill the light zone. The light zone contains a rich network of follicular dendritic cells (FDC) that have the capacity to take up antigen and hold this on their surface for periods of more than a year. The antigen is held as an immune complex in a native unprocessed form; but the antigen may be taken up from FDC by B cells, which can process this and present it to T cells. Centrocytes appear to be selected by their ability to interact with antigen held on FDC. There is a high death rate among centrocytes in vivo, and when these cells are isolated in vitro, they undergo apoptosis within hours on culture. The onset of apoptosis can be delayed by cross-linking centrocytes' surface Ig, and long-term survival is achieved by signalling through their surface CD40. After activation through CD40 the centrocytes increase their surface Ig and acquire characteristics of memory and processing of antigen held on FDC and its presentation to T cells that can be induced to express CD40 ligand at the point of cognate interaction. Other signals that induce a proportion of germinal center cells to become plasma cells have also been described. Germinal centers persist for about 3 weeks following immunization, but after this, memory B blasts continue to proliferate in follicles throughout the months of T cell-dependent antibody responses. These cells are probably the source of plasma cells and memory cells required to maintain long-term antibody production and memory after the first 3 weeks of T cell-dependent antibody responses.
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Structure of Peptides Associated with Class I and Class II MHC Molecules
Vol. 12 (1994), pp. 181–207More LessClass I and class II molecules encoded by genes within the major histocompatibility complex play a central role in regulation of immune responses through their ability to bind and display small peptides derived from foreign antigens. Within the last few years, considerable progress has been made in understanding the structures of class I and class II MHC molecules, as well as the features of the peptides that are their principal ligands. This review summarizes this information and describes how it accounts for both the specificity and degeneracy of peptide binding. It also considers how the origin and structural features of peptides that have been isolated from MHC molecules, so-called “naturally processed” peptides, have provided insight into the pathways through which the peptides are produced. Finally, the use of new structural information and techniques for peptide characterization for the identification of peptides that comprise epitopes for individual antigen-specific T cells are considered.
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Lymphokine Production by Human T Cells in Disease States
Vol. 12 (1994), pp. 227–257More LessA large body of evidence suggests the existence of polarized human T cell responses, reminiscent of Th1 and Th2 subsets described for mouse T cells. Human Th1-like cells preferentially develop during infections by intracellular bacteria, protozoa, and viruses, whereas Th2-like cells predominate during helminthic infestations and in response to common environmental allergens. The cytokine profile of “natural immunity” evoked by different offending agents in the context of different host genetic backgrounds appears to be a critical factor in determining the phenotype of the subsequent specific response.
Strongly polarized human Th1-type and Th2-type responses not only play different roles in protection, they can also promote different immunopathological reactions. Th1-type responses appear to be involved in organ specific autoimmunity, in contact dermatitis, and in some chronic inflammatory disorders of unknown etiology. In contrast, in genetically predisposed hosts, Th2-type responses against common environmental allergens are responsible for triggering of allergic atopic disorders. Altered profiles of lymphokine production may account for immune dysfunctions in some primary or acquired immunodeficiency syndromes. The role of lymphokines produced by T cells in the pathogenesis of systemic autoimmune disorders is less clear. Further work is also required to better clarify the role of T cell-derived lymphokines in protecting against tumors or in favoring their development.
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Assembly, Transport, and Function of MHC Class II Molecules
Vol. 12 (1994), pp. 259–291More LessMHC class II molecules assemble in the endoplasmic reticulum in a chaperone-mediated fashion to form a nine-chain structure consisting of three alpha beta dimers associated with an invariant chain trimer. This complex is transported through the Golgi apparatus and into the endosomal system. The signal for endosomal targeting resides in the cytoplasmic tail of the invariant chain. Current evidence argues that the segregation of the class II-invariant chain complex from the constitutive pathway of membrane protein transport occurs in the trans-Golgi network. However, class II-invariant chain complexes that reach the cell surface are also rapidly internalized into endosomes. Within the endosomal system, probably in a late endosome/pre-lysosome, the invariant chain is degraded, releasing alpha beta dimers that bind peptides predominantly derived from endocytosed proteins. Evidence suggests that many of these peptides are actually generated in lysosomes. The precise mechanisms involved in forming class II-peptide complexes are unclear, although the existence of antigen-processing mutants argues that additional gene products, at least one of which is encoded in the MHC, are involved. After binding peptides, class II molecules are transported by an unknown route to the cell surface, where their primary function of presenting antigenic peptides to CD4+ T cells is carried out.
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Lymphocyte Ontogeny and Activation in Gene Targeted Mutant Mice
K. Pfeffer, and T. W. MakVol. 12 (1994), pp. 367–411More LessGene targeting by homologous recombination in pluripotent embryonic stem cells enabled the systematic creation of mouse strains with defined genetic alterations. During the past few years a rapidly growing number of gene targeted mice has provided new insights into development, selection, activation, and signaling of T and B cells, as well as into the functions of cytokines. Here we discuss the present state of targeting technology and summarize the phenotypic changes observed in gene targeted mouse strains of immunological interest. These data allow us for the first time to define genetic checkpoints in lymphocyte development that are crucial for the orderly progression of T and B cells through ontogeny and for the generation of an immune response.
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Antigen Analogs/MHC Complexes as Specific T Cell Receptor Antagonists
Vol. 12 (1994), pp. 413–431More LessRecent studies demonstrated that antigen analogs can act as powerful and specific inhibitors of T cell activation, leading to the formulation of the concept that antigen analog/MHC complexes may act as antagonists of the T cell receptor (TCR). TCR antagonism appears to be associated with engagement of the TCR below a crucial affinity threshold necessary for full T cell activation. Studies addressing the molecular mechanism of this effect suggest that TCR antagonists could act by interfering with membrane-related events (such as proper receptor clustering) that might precede intracellular signaling. Discovery of the TCR antagonism phenomenon also suggested a possible rational approach to antigen-specific immunointervention in allergies and autoimmune diseases. The feasibility of such an approach is now being actively investigated. Finally, TCR antagonist peptides may provide a useful tool to probe TCR-peptide/MHC interactions involved in the process of thymic education.
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Making Antibodies by Phage Display Technology
Vol. 12 (1994), pp. 433–455More LessAntibody fragments of predetermined binding specificity have recently been constructed from repertoires of antibody V genes, bypassing hybridoma technology and even immunization. The V gene repertoires are harvested from populations of lymphocytes, or assembled in vitro, and cloned for display of associated heavy and light chain variable domains on the surface of filamentous bacteriophage. Rare phage are selected from the repertoire by binding to antigen; soluble antibody fragments are expressed from infected bacteria; and the affinity of binding of selected antibodies is improved by mutation. The process mimics immune selection, and antibodies with many different binding specificities have been isolated from the same phage repertoire. Thus human antibody fragments have been isolated with specificities against both foreign and self antigens, including haptens, carbohydrates, secreted and cell surface proteins, viral coat proteins, and intracellular antigens from the lumen of the endoplasmic reticulum and the nucleus. Such antibodies have potential as reagents for research and in therapy.
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Selective Events in T Cell Development
E Robey, and B J FowlkesVol. 12 (1994), pp. 675–705More Less
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Previous Volumes
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Volume 42 (2024)
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Volume 41 (2023)
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Volume 40 (2022)
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Volume 39 (2021)
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Volume 38 (2020)
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Volume 37 (2019)
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Volume 36 (2018)
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Volume 35 (2017)
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Volume 34 (2016)
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Volume 33 (2015)
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Volume 32 (2014)
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Volume 31 (2013)
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Volume 30 (2012)
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Volume 29 (2011)
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Volume 28 (2010)
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Volume 27 (2009)
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Volume 26 (2008)
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Volume 25 (2007)
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Volume 24 (2006)
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Volume 23 (2005)
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Volume 22 (2004)
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Volume 21 (2003)
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Volume 20 (2002)
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Volume 19 (2001)
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Volume 18 (2000)
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Volume 17 (1999)
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Volume 16 (1998)
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Volume 15 (1997)
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Volume 14 (1996)
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Volume 13 (1995)
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Volume 12 (1994)
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Volume 11 (1993)
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Volume 10 (1992)
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Volume 9 (1991)
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Volume 8 (1990)
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Volume 7 (1989)
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Volume 6 (1988)
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Volume 5 (1987)
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Volume 4 (1986)
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Volume 3 (1985)
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Volume 2 (1984)
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Volume 1 (1983)
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Volume 0 (1932)