Showing papers in "Immunologic Research in 1999"

The paradigm of Th1 and Th2 cytokines: its relevance to autoimmunity and allergy.

Abstract: In the past few years, considerable evidence has accumulated to suggest the existence of functionally polarized responses by the CD4+ T helper (Th)—and the CD8+ T cytotoxic (Tc)—cell subsets that depend on the cytokines they produce. The Th1 and Th2 cellular immune response provide a useful model for explaining not only the different types of protection, but also the pathogenic mechanisms of several immunopathological disorders. The factors responsible for the polarization of specific immune response into a predominant Th1 or Th2 profile have been extensively investigated in mice and humans. Evidence has accumulated from animal models to suggest that Th1type lymphokines are involved in the genesis of organ-specific autoimmune diseases, such as experimental autoimmune uveitis, experimental allergic encephalomyelitis, or insulin-dependent diabetes mellitus. Accordingly, data so far available in human diseases favor a prevalent Th1 lymphokine profile in target organs of patients with organ-specific autoimmunity. By contrast, Th2-cell predominance was found in the skin of patients with chronic graft-versus host disease, progressive systemic sclerosis, systemic lupus erythematosus, and allergic diseases. The Th1/Th2 concept suggests that modulation of relative contribution of Th1 or Th2-type cytokines regulate the balance between protection and immunopathology, as well as the development and/or the severity of some immunologie disorders. In this review, we have discussed the paradigm of Th1 and Th2 cytokines in relation to autoimmunity and allergy.

CD28/CTLA-4 and CD80/CD86 families: signaling and function.

Abstract: T cell stimulation in the absence of a second, costimulatory signal can lead to anergy or the induction of cell death. CD28 is a major T cell costimulatory receptor, the coengagement of which can prevent anergy and cell death. The CD28 receptor is a member of a complex family of polypeptides that includes at least two receptors and two ligands. Cytotoxic lymphocyte-associated molecule-4 (CTLA-4, CD152) is the second member of the CD28 receptor family. The ligands or counterreceptors for these two proteins are the B7 family members, CD80 (B7-1) and CD86 (B7-2). This article reviews the CD28/CTLA4 and CD80/CD86 families, and outlines the functional outcomes and biochemical signaling pathways recruited after CD28 ligation.

Lymphoid neo-organogenesis: lymphotoxin's role in inflammation and development.

Abstract: Lymphoid organ development and inflammation have previously been considered as distinct mechanistically and functionally. In recent years, it has been realized that these phenomena have much in common. This insight has been gained from the recognition that cytokines of the lymphotoxin (LT)/tumor necrosis factor (TNF) family are involved in both processes. The members of the family, LT-alpha, LT-beta, and TNF-alpha, and their multiple receptors participate combinatorially in lymphoid organ development and chronic inflammation. When inflammation that arises in microbial infection or autoimmune disease becomes chronic, it can take on the appearance of organized lymphoid tissue and has been called a tertiary lymphoid organ. Data with transgenic and knockout mice suggest that the process is cytokine-mediated and could be called "lymphoid neo-organogenesis." LT as LT-alpha3 and LT-alpha1beta2 plays a key role in these processes. Data obtained in vitro in an endothelial cell line and in vivo in transgenic and knockout mice indicate that LT influences these events through induction of adhesion molecules such as E-selectin adhesion molecule (ELAM), vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), mucosal addressin cellular adhesion molecule (MAdCAM), and peripheral node addressin (PNAd), and chemokines.

The immune system in the elderly: II. Specific cellular immunity.

Abstract: Numerous changes occur in the immune system with advancing age, probably contributing to the decreased immunoresponsiveness in the elderly. These changes are often associated with important clinical manifestations such as increased susceptibility to infection and cancer frequently observed in the elderly population. Although both cellular and humoral immune responses are modified with advancing age, much of the decrease in immunoresponsiveness seen in elderly populations is associated with changes in T cell responses. The loss of effective immune activity is largely due to alterations within the T cell compartment which occur, in part, as a result of thymic involution. Substantial changes in both the functional and phenotypic profiles of T cells have been reported with advancing age. In fact, two prominent features of immunosenescence are altered T cell phenotype and reduced T cell response. One of the most consistent changes noted in T cells with advancing age is the decrease in the proportion of naive T cells with a concomitant increase in T cells with an activated/memory phenotype. In addition, there is evidence that the T cell population from aged individuals is hyporesponsive. The observed functional changes include decreased responsiveness to T cell receptor stimulation, impaired T cell proliferative capacity, a decline in the frequency of CD4+ T cells producing IL-2 and a decreased expression in IL-2 receptors. These latter findings probably explain the loss of proliferative capability of T cells from aged individuals. There is also evidence of a decrease in the early events of signal transduction, decreased activation-induced intracellular phosphorylation, and decreased cellular proliferative response to T cell receptor stimulation. The present review analyzes the main changes of the T cell compartment characterizing immunosenescence and discusses the possible mechanisms underlying these disregulations and their clinical implications.

The immune system in the elderly: III. Innate immunity

Abstract: The capability to cope with infectious agents and cancer cells resides not only in adaptive immune responses against specific antigens, mediated by T and B lymphocytes clonally distributed, but also in natural immune reactions. These innate defence mechanisms include chemotaxis, phagocytosis, natural cytotoxicity, cell interactions, and soluble mediators or cytokines. However, specific and natural immune mechanisms are always closely linked and interconnected, providing the primary defense against pathogens. The Authors discuss the main changes observed with advancing age in granulocytes and natural killer (NK) cell activity, in the expression and function of adhesion molecules, and in the pattern of cytokine production. Since phagocytic function is the primary mechanism through which the immune system eliminates most extracellular pathogenic microorganisms, analysis of this function is of clinical importance. Neutrophils from aged subjects often exhibit a diminished phagocytic capacity, as well as a depressed respiratory burst, notwithstanding an activated state. The activity of NK cells during aging has been studied extensively and different results have been reported. The most consistent data indicate an increase in cells with high NK activity with advancing age. Cells from healthy centenarians can efficiently kill target cells. This finding seems to suggest that innate immunity and in particular NK cell activity, is not heavily deteriorated with age. Conversely, a low NK activity is a predictor of impending morbidity. Immunosenescence is associated with increased expression of several cell adhesion molecules (CAM) resulting in an augmented capacity to adhere. Finally, also the cytokine network, responsible for differentiation, proliferation, and survival of lymphoid cells, undergoes complex changes with age. The main findings are a Th1 to Th2 cytokine production shift and an increased production of proinflammatory cytokines, which could explain many aspects of age-associated pathological events, such as atherosclerosis and osteoporosis.

Immune response to staphylococcal superantigens.

Abstract: Staphylococcal exotoxins, staphylococcal enterotoxins A-E (SEA-SEE), and toxic shock syndrome toxin- (TSST-1) are potent activators of the immune system and cause a variety of diseases in humans, ranging from food poisoning to shock. These toxins are called superantigens because of their ability to polyclonally activate T cells at picromolar concentrations. Superantigens bind to both MHC class II molecules and specific Vbeta regions of the T cell receptor, leading to the activation of both antigen-presenting cells and T lymphocytes. These interactions lead to excessive production of proinflammatory cytokines and T cell proliferation, causing clinical symptoms that include fever, hypotension, and shock. Recent studies suggest that staphylococcal superantigens may also be involved in the pathogenesis of arthritis and other autoimmune disorders. This review summarizes the in vitro and in vivo effects of staphylococcal enterotoxins and TSST-1, recent progress with the use of transgenic knockout mice to identify key mediators and receptors involved in superantigen-induced shock, and therapeutic agents to mitigate the toxic effects of staphylococcal superantigens.

Regulation of inducible gene expression by the transcription factor NF-kappaB.

Abstract: The transcription factor NF-kappaB plays a critical role in regulating inducible gene expression in immune responses. The activation of NF-kappaB is regulated at multiple levels, probably reflecting a need to maintain a tight control of its activity. We have recently discovered that direct phosphorylation of NF-kappaB itself is essential for its transcriptional activity and that phosphorylation acts as a switch to determine association of nuclear NF-kappaB with histone acetylases vs deacetylases.

The immune system in the elderly: I. Specific humoral immunity.

Abstract: Profound and complex changes in the immune response occur during the aging process Immunosenescence is reflected by a sum of disregulations of the immune system and its interaction with other systems Many of the changes would appear to implicate age-related deficiencies of the immune responses The term immunosenescence designates therefore a sort of deterioration of the immune function which is believed to manifest itself in the increased susceptibility to cancer, autoimmune disease, and infectious disease Evidence has been accumulating from several studies which suggest an association between immune function and individual longevity However, there are observations, especially in very old healthy people, that several immune functions are unexpectedly well preserved and substantially comparable to those observed in young subjects These findings raise the question of whether the alterations that can be observed in the immune parameters of the elderly are a cause or a result of underlying disease processes Moreover, studies on centenarians revealed a remodeling of the immune system rather than a deterioration, suggesting that the changes observed during immunosenescence do not correspond to immunodeficiency The underlying mechanisms of these events are however still unclear The purpose of the present review is to assess the status of research on the immunobiology of aging In this first section, we focus attention on the B cell biology of aging In clinical practice, the changes in humoral immune responsiveness and antibody-mediated defense mechanisms could greatly influence the incidence and outcome of bacterial infections and autoimmune diseases as well as the response to vaccines

Immunobiology of human vascular endothelium.

Abstract: The author's laboratory studies interactions between human T lymphocytes and vascular endothelial cells (EC) Our work is organized around three hypotheses First, we propose that vascular EC can initiate secondary (ie, recall) immune reactions by presenting antigenic peptide-major histocompatibility complex (MHC) complexes to those circulating memory T cells whose cognate antigen is locally present within a peripheral tissue, eg, as a consequence of infection or allogeneic transplantation In this way, EC can increase the efficiency of immune surveillance Second, we propose that T cell signals, both secreted (eg, cytokines) and contact-dependent (eg, CD40 ligand), activate new gene expression in EC that induce the capacity to perform new effector functions, such as leukocyte recruitment and activation or initiation of intravascular coagulation In this way, EC can participate as effector cells for cell-mediated immune reactions Third, we propose that EC are major targets of immune-mediated injury Consequently, increasing resistance of endothelium to immune effector mechanisms may protect tissues from damage, eg, in allograft rejection These three hypotheses are explored through in vitro experiments, through analyses of human tissue specimens, and through in vivo studies employing novel human-mouse chimeric animals

Murine mercury-induced autoimmunity: a model of chemically related autoimmunity in humans.

Abstract: Human exposure to certain compounds or therapeutic drugs can result in the development of an autoimmune syndrome. Mercury (Hg) induced autoimmunity is one of the few animal models in which administration of a chemical induces a specific loss of tolerance to self-antigens. After receiving subtoxic doses of Hg or other heavy metals, susceptible mouse strains rapidly develop highly specific antibodies to nucleolar antigens. In addition, these animals display a general activation of the immune system, especially pronounced for the Th2 subset and a transient glomerulonephritis with immunoglobulin deposits. Like many human autoimmune diseases, this syndrome is associated with the expression of susceptible major histocompatibility complex (MHC) classII genes. In this article, we review the essential features of this model, and we discuss the putative mechanisms by which Hg creates such a severe immune dysfunction.

Role of cytokines in pulmonary antimicrobial host defense.

Abstract: Host defense of the lung is characterized by a fine balance between the generation of a vigorous inflammatory response to clear pathogens and maintenance of the integrity of the alveolar gas-exchange surface. The magnitude of the inflammatory response is therefore tightly regulated by pro- and anti-inflammatory cytokine mediators. This article summarizes current information on the roles of specific cytokines in pneumonia, with particular emphasis on ongoing investigations into the role of innate immunity in bacterial and fungal pneumonia.

Cd43, a molecule with multiple functions

Abstract: To initiate a specific immune response, lymphoid cells integrate a variety of signals generated through the orchestrated interaction of multiple cell surface molecules with their counter-receptors. As a result of the specific recognition of the antigen through antigenspecific receptors, and of the monitoring of their particular environment through the so-called coreceptor molecules, lymphoid cells go through elaborate processes of maturation and activation, contributing to the plasticity and sensitivity of immune response. CD43 is the major sialic acid rich protein on the surface of lymphocytes. However, the specific roles of this protein in different lymphoid cells under normal physiological conditions remain largely unknown. In this review we will mainly focus on the recent advances concerning the functions of this molecule as a coreceptor of different lymphoid cells as well as on the participation of this molecule in different pathologies.

Eosinophils, ribonucleases and host defense: solving the puzzle

Abstract: The eosinophil ribonucleases eosinophil-derived neurotoxin (EDN/ RNase 2) and eosinophil cationic protein (ECP/RNase 3) are among the major secretory effector proteins of human eosinophilic leukocytes, cells whose role in host defense remains controversial and poorly understood. We have recently described the unusual manner in which this ribonuclease lineage has evolved, with extraordinary diversification observed in primate as well as in rodent EDNs and ECPs. The results of our evolutionary studies suggest that the EDN/ ECP ribonucleases are in the process of being tailored for a specific, ribonuclease-related goal. With this in mind, we have begun to look carefully at some of the intriguing associations that link eosinophils and their ribonucleases to disease caused by the single-stranded RNA viral pathogen, respiratory syncytial virus (RSV). Recent work in our laboratory has demonstrated that eosinophils can mediate a direct, ribonuclease-dependent reduction in infectivity of RSV in vitro, and that EDN can function alone as an independent antiviral agent. The results of this work have led us to consider the possibility that the EDN/ECP ribonucleases represent a heretofore unrecognized element of innate and specific antiviral host defense.

The hereditary hemochromatosis gene (HFE): a MHC class I-like gene that functions in the regulation of iron homeostasis.

Abstract: The iron overload disorder, hereditary hemochromatosis, is one of the most common genetic diseases of individuals of Northern European descent. The disorder is characterized by the progressive accumulation of dietary iron in the major organs of the body, which if not diagnosed, leads to numerous medical maladies and eventually death. The locus for this disorder was mapped by genetic linkage to the short arm of chromosome over twenty years ago, but it was not until 1996 that the gene for this disorder was cloned by an identity-by-descent positional cloning approach. The gene, called HFE, encodes a major histocompatibility complex (MHC) class I-like protein that is mutated in approx 85% of all individuals known to have hereditary hemochromatosis (HH). Since the cloning of the HFE gene, considerable work has been carried out which has furthered our understanding of the genetics of this prevalent disorder. In addition, with the identification of the transferrin receptor as a protein capable of interacting with HFE we are now beginning to understand how a protein with the structural characteristics of an MHC class I molecule can influence cellular iron homeostasis.

The interaction of intestinal epithelial cells and intraepithelial lymphocytes in host defense.

Abstract: Intestinal intraepithelial lymphocytes (i-IEL) are located at the basolateral surfaces of intestinal epithelial cells (i-EC) and play important roles in the homeostasis of intestinal microenvironment. i-IEL comprise unique T cell populations including CD4-CD8αα+ T cells expressing T cell receptor (TCR)αΒ or TCRγδ and CD4+ CD8αα+ T cells expressing TCR αΒ. We show here that CD4+ CD8αα+ i-IEL belongs to Th1 type T cells capable of responding to self-MHC class I on i-EC and that a significant fraction of i-IEL expressed Fas ligand (Fas-L) and induced apoptosis in the i-EC via Fas-dependent pathway. i-IEL may recognize and eliminate the effete i-EC for homeostatic regulation of intestinal epithelia. The interaction of i-EC and i-IEL through E-cadherin/αEΒ7 integrin is important for homing and maintenance of i-IEL in intestine.Listeria monocytogenes are also known to interact with E-cadherin on i-EC and invade into the epithelial cells. Invasion ofL. monocytogenes into i-EC activated NFk-B and subsequently up-regulated the expression of IL-15 gene, which has a NFk-B binding site at the promoter region. i-IEL, especially γδ T cells, were significantly activated to produce Th1 type cytokines at the early stage after oral infection withL. monocytogenes in mice and rats. The activation of i-IEL coincided with a peak response of IL-15 production by i-EC after infection. Taken together, mutual interaction of i-IEL and i-EC may be important not only for homeostatic regulation but also host defense against microbial infection in intestine.

HLA-DM and the MHC class II antigen presentation pathway.

Abstract: The MHC class II antigen processing pathway provides a mechanism to selectively present peptides generated in the endosomal compartments of antigen presenting cells to CD4+ T cells. Transport of newly synthesized class II molecules to the endosomal pathway requires the function of an accessory protein, invariant chain, which contains a region that interacts directly with the class II peptide binding site. Release of invariant chain and peptide loading by class II molecules are facilitated by a second accessory protein, HLA-DM. This MHC-encoded membrane protein catalyzes peptide exchange reactions, influencing the repertoire of peptides that are available for recognition by T cells.

MHC class I restricted T cell responses to Listeria monocytogenes, an intracellular bacterial pathogen.

Abstract: Studies of the murine immune response to infection with the intracellular bacterial pathogenListeria monocytogenes have provided a wealth of information about innate and acquired immune defenses in the setting of an infectious disease. Our studies have focused on the MHC class I restricted, CD8+ T cell responses of Balb/c mice toL. monocytogenes infection. Four peptides that derive from proteins thatL. monocytogenes secretes into the cytosol of infected cells are presented to cytotoxic T lymphocyte (CTL) by the H2-Kd major histocompatibility complex (MHC) class I molecule. We have found that bacterially secreted proteins are rapidly degraded in the host cell cytosol by proteasomes that utilize, at least in part, the N-end rule to determine the rate of degradation. The MHC class I antigen processing pathway is remarkably efficient at generating peptides that bind to MHC class I molecules. The magnitude of in vivo T cell responses, however, is influenced to only a small degree by the amount of antigen or the efficiency of antigen presentation. Measurements of in vivo T cell expansion followingL. monocytogenes infection indicate that differences in the sizes of peptide-specific T cell responses are more likely owing to differences in the repertoire of naive T cells than to differences in peptide presentation. This notion is supported by our additional finding that dominant T cell populations express a more diverse T cell receptor (TCR) repertoire than do subdominant T cell populations.

The influence of base sequence on the immunostimulatory properties of DNA.

Abstract: DNA is a complex macromolecule whose immunological properties vary with base sequences. As shown with synthetic oligonucleotides, potent immune stimulation results from six base motifs called CpG motifs or immunostimulatory sequences (ISS). These sequences center on an unmethylated CpG dinucleotide and occur much more commonly in bacterial DNA than mammalian DNA. As such, CpG motifs may function as a danger signal to stimulate B cell activation and cytokine production. In addition to CpG motifs, runs of deoxyguanosine (dG) residues in DNA can induce B cell activation and promote macrophage cytokine expression by adjacent CpG motifs. The array of these sequences may determine the overall immune activity of a DNA molecule and affect such processes as host defense against infection as well as the use of plasmids and synthetic oligonucleotides to treat disease.

The molecular basis of T cell differentiation

Abstract: Our laboratory has studied the molecular basis of T helper cell differentiation. We have used reporter transgenic mice, selective hybridization techniques, and studies of cell signaling to show that a complex pattern of gene expression is reprogrammed as the decision is made to become either a Th1 or Th2 cell. Many of these components have been identified, and their mechanisms of action elucidated. Understanding these mechanisms is likely to lead in the long-term to ways to intervene in these processes and, therefore, to direct immune response in therapeutically useful directions.

Autoreactive T cells in murine lupus

Abstract: The conventional paradigm to explain systemic lupus erythematosus (SLE) is that disease results from tissue deposition of pathogenic autoantibodies and immune complexes, secondary to activation of autoreactive B cells in the context of help from αΒ T cells. Recent work in murine lupus has confirmed this notion and demonstrated that autoantigen-specific αΒ T cells are absolutely required for full penetrance of disease, with such autoreactive αΒ T cells, even in Fasintact mice, likely arising from defects in peripheral tolerance. These studies have also revealed a network of regulation that also involves nonclassical pathogenic and downregulatory αΒ and γδ T cells, suggesting that the lupus immune system involves more complex interactions than the conventional paradigm suggests.

Regulation of integrin function by T cell activation: points of convergence and divergence.

Abstract: Lymphocyte adhesiveness is dynamically regulated in response to conditions in the extracellular environment. One mechanism of regulation of integrin adhesion receptors involves a rapid, but transient, increase in integrin function upon T lymphocyte activation. These integrin activating signals can be initiated either via ligation of Ig superfamily members that are coupled to tyrosine kinase cascades, such as the CD3/T cell receptor, CD2, and CD28, or by G proteincoupled receptors for chemokines. Analysis of integrin activation induced by CD3/TCR, CD2 and CD28 suggests a critical role for phosphoinositide 3-OH kinase (PI 3-K). This review summarizes recent insights into PI 3-K-dependent regulation of integrin function in leukocytes, including the mechanisms by which these receptors are coupled to PI 3-K, and potential downstream effectors of PI 3-K that regulate integrin-mediated adhesion in leukocytes.

Interleukin 12 and innate molecules for enhanced mucosal immunity.

Abstract: Recent strategies for understanding the mechanisms underlying mucosal immune responses and subsequent development of mucosal vaccines for induction of targeted immunity now include cytokines and molecules of innate immunity These studies have shown that cytokines influencing the development of T helper (Th) cells differentially affect the outcome of mucosal vs systemic immune responses to mucosal vaccines Serum antigen-specific antibody (Ab) responses were enhanced when either IL-6 or IL-12 was mucosally administered with a protein antigen, while only IL-12 induced antigen-specific mucosal IgA Ab responses Mucosal IL-6 and IL-12 also affected the type of Th cell responses induced by CD4+ T cells from mice that received IL-12 secreted larger amounts of IFN-γ and IL-6 when compared with mice nasally treated with IL-6 Discrepancies in the ability to enhance mucosal or systemic immune responses were also observed when human neutrophil peptide (HNP) defensins or lymphotactin were nasally coadministered with protein antigens Only lymphotactin promoted mucosal secretory IgA (S-IgA) Ab responses while both lymphotactin and defensins enhanced systemic immunity to mucosally co-administered protein antigens Mixed antigen-specific Th1-and Th2-type CD4+ T cell responses were induced in the systemic compartment by both lymphotactin and the mixture of HNP-1, HNP-2, and HNP-3 defensins However, HNPs failed to significantly enhance cytokine secretion by mucosally derived, antigen-specific CD4+ T cells relative to those isolated from the systemic compartment In summary, these studies clearly show that IL-12 and lymphotactin are able to trigger S-IgA Ab responses and provide new avenues for the design of safe and targeted mucosal vaccines

Death and destruction of activated T lymphocytes.

Abstract: The massive clonal expansion that occurs during an antigen-specific immune response results in the flooding of immune organs with activated T lymphocytes. At the end of a specific response, the vast majority of these activated T cells are cleared from the immune system. The T cells receive signals through specific death receptors that are expressed as a result of activation. Death receptors transmit their apoptotic signals through the activation of caspases. Function of the death receptors is intimately linked to cell-cycle control, and many cell-cycle control proteins are caspase substrates. Among CD8+ T cells, apoptotic death occurs at a specific site, the sinusoids of the liver. The liver appears to contain a mechanism for the trapping and killing of activated T cells, rendering it an immunologically privileged site.

Thiol oxidation and reduction in MHC-restricted antigen processing and presentation.

Abstract: Major histocompatibility complex (MHC) class I molecules are assembled in the endoplasmic reticulum (ER) as a trimer of the class I heavy chain, beta2 microglobulin (beta2m), and a short peptide. Assembly occurs in a complex with additional noncovalently associated proteins, which include the thiol oxidoreductase, ERp57. This molecule facilitates the formation of the correct disulfide bonds in glycoproteins as they fold in the ER and may play a key role in assembling a stable MHC class I-peptide complex. In the endocytic pathway, reduction of protein disulfide bonds is important for the generation of MHC class II-peptide complexes. This process is catalyzed by a gamma-interferon-inducible thiol reductase (GILT). The possible requirement for catalysis of disulfide bond formation in MHC class I-restricted antigen processing and the known requirement for disulfide bond reduction in MHC class II-restricted antigen processing present interesting examples of the adaptation of cellular "housekeeping" functions to facilitate immune responses.

Immunological self/nonself discrimination: integration of self vs nonself during cognate T cell interactions with antigen-presenting cells.

Abstract: The hypothesis is presented that immunological integration of nonefficacious vs efficacious T cell antigen receptor (TCR) signals are foundational for self/nonself discrimination and that multiple integrative mechanisms are intrinsic to the molecular to molar organization of an adaptive immune response. These integrative mechanisms are proposed to adaptively regulate expression of costimulatory signals, such that foreign proteins are associated with the expression of costimulatory signals, whereas self-proteins are associated with the lack of costimulatory signaling. Overall, this model offers several unique contributions to the study of immunology. First, this model postulates that cognate TCR/major histocompatibility complex (MHC) interactions are sufficient to adaptively mediate immunological self/nonself discrimination. This model thereby offers a unique alternative to models that largely rely on innate immunity to prime immune discrimination. Second, the integrative model argues that the immune system can simultaneously reinforce self-tolerance and promote immunity to foreign organisms at the same time and in the same location. Many alternative models presume that pathogenic self-reactive T cells do not exist at the outset of an immune response against foreign agents. Third, the integrative model uniquely predicts relationships between immunodeficiency and autoimmune pathogenesis. Fourth, this model illustrates the regulatory advantages of cognate antigen presenting cell (APC) systems (i.e., T cell or B cell APC) compared to nonspecific APC. Cognate APC systems together with the respective clonotypic responders may comprise a fundamental “network” of lymphoid cells. Such networks would have clone-specific regulatory capabilities and may be central for immunological self/nonself discrimination. Fifth, this model provides an explanation for “infectious” tolerance without creating specialized subsets of “suppressor” or “regulatory” T cells. Each mature T cell retains the potential to reinforce tolerance or mediate immunity, depending on the specific antigenic cues present in the immediate environment.

New gut associated lymphoid tissue "cryptopatches" breed murine intestinal intraepithelial T cell precursors

Abstract: Numerous mouse intraepithelial T cells (IEL) bearing either TCR-alphabeta or TCR-gammadelta have been shown to develop somewhere in the intestinal mucosa without passing through the thymus. However, just where these T cells develop has been much less clear and has remained an open question to date. In an effort to investigate this issue, we carried out immunohistochemical study on the murine gastrointestinal tract and identified numerous tiny lymphoid tissues (approximately 1,650 tissues/intestine) in the cryptal region of the small and large intestinal mucosa except for the stomach in which clusters of c-kit+ IL-7R+ Thy1+ lympho-hemopoietic progenitors accumulated (cryptopatches). The cryptopatch cells isolated from the small intestine, which were c-kit positive (c-kit+) but lineage marker negative (Lin-), gave rise to TCR-alphabeta and TCR-gammadelta IELs following in vivo transfer or tissue engraftment into 2 Gy-irradiated severe combined immunodeficient mice. In contrast, cells isolated from Peyer's patches and mesenteric lymph nodes, which belong in the same intestinal immune compartment but lack c-kit+Lin- cells, failed to do so. These results in conjunction with the findings of electron microscopic analysis provide direct evidence of a local intestinal T cell precursor that develops in the cryptopatches.

The role of tapasin in MHC class I antigen assembly.

Abstract: The discovery of tapasin has shed new light on the mechanisms of major histocompatibility complex (MHC) class I assembly in the endoplasmic reticulum (ER). Tapasin appears to play an important role in the stable assembly of class I molecules with peptide, however, the precise function of tapasin remains elusive. The pursuit of tapasin function is complicated by the observation that tapasin is not required for successful antigen presentation by all class I molecules. In addition, current data suggest that the putative role of tapasin as a bridging molecule between transporter associated with antigen presentation (TAP) and class I is only of minor importance in tapasin action, and tapasin’s major role appears to be as an active cofactor in the assembly of class I. Furthermore, it is clear that class I molecules can follow multiple pathways for successful assembly in the ER. These pathways may or may not include the interaction of class I molecules with the accessory proteins tapasin, calreticulin, ERp57, or TAP. I would like to suggest that the particular pathway utilized by a given class I molecule depends more upon the availability of appropriate peptides rather than on an intrinsic property of the class I molecule, and that tapasin may serve a peptide editing function.

The development of CD4+ T effector cells during the type 2 immune response.

Abstract: Multiple pathways may be involved in the development of interleukin 4 (IL-4) producing T helper (Th) cells and the associated type 2 immune response. Increasing evidence suggests that the strength of signals delivered to the T cell may favor the development of the type 2 response. In contrast, antigen-presenting cell-(APC) derived stimuli produced following pattern recognition receptor binding during the innate response promotes the development of interferon-γ (IFN-γ) producing cells and the associated type 1 immune response. In many cases, the balance between increased signaling strength and the innate response may determine whether the type 2 response develops. T cell receptor (TCR), CD4, and costimulatory molecule interactions may all contribute to signal strength, but the type 2 immune response may be particularly dependent on the availability of coreceptor and costimulatory molecule interactions. B7 ligand interactions are required for the development of the type 2 immune response and interaction of CD28 with either B7-1 or B7-2 can provide sufficient signals for its initiation. In B7-2-deficient mice, the initial type 2 immune response is intact, but the response is not sustained, suggesting that B7-2 is important at later stages of the type 2 immune response. The roles of CD28 and CTLA-4 during the type 2 response remain unclear. The type 2 response to infectious pathogens is pronounced in CD28-/-mice, suggesting that other costimulatory molecule interactions can substitute for CD28 for the development of IL-4 producing T cells and the associated type 2 immune response.

The role of self-recognition in receptor repertoire development

Abstract: The role of self-antigen recognition in the development of T and B cells of the adaptive immune system has been studied in several different ways. We have shown that CD4 T cells are selected on selfpeptide:self-MHC class II ligands, and in the periphery, they are sustained by contact with the same or similar ligands. We have also observed that B cells are positively selected on unknown and presumed self-ligands. We have used this information to explore autoimmune diseases as well. Finally, we have recently identified the innate immune system as playing a crucial role in regulating expression of costimulatory molecules that are required for induction of adaptive immune responses.

Transposition mediated by rag1 and rag2 and the evolution of the adaptive immune system

Abstract: The RAG1 and RAG2 proteins together initiate V(D)J recombination by performing cleavage of chromosomal DNA adjacent to antigen receptor gene segments. Like the adaptive immune system itself,RAG1 andRAG2 are found only in jawed vertebrates. The hypothesis thatRAG1 andRAG2 arose in evolution as components of a transposable element has received dramatic support from our recent finding that the RAG proteins are a fully functional transposase in vitro. This result strongly suggests that antigen receptor genes acquired their unusual structure as a consequence of the insertion of a transposable element into an ancestral receptor gene by RAG1 and RAG2 approx 450 million years ago.