Showing papers in "Immunologic Research in 1996"
TL;DR: Interventions to specifically eliminate or modify the response of donor T cells to alloantigens in order to reduce GVHD may obviate the need for T cell depletion in clinical BMT and thus avoid the increased risk of relapse of malignancy and impairment of donor cell engraftment.
Abstract: Graft-versus-host disease (GVHD) is the major complication after allogeneic bone marrow transplantation (BMT) and is initiated by alloreactive donor T cells recognizing foreign histocompatibility antigens of the host. There is now substantial experimental and clinical evidence to implicate a dysregulation of cytokine networks as a primary cause for the induction and maintenance of GVHD. In this article, current knowledge of the involvement of cytokines in GVHD is reviewed. The balance between type 1 cytokines (interleukin-2, interferon-gamma) and type 2 cytokines (interleukin-4, interleukin-10) is hypothesized to govern the extent to which a cell-mediated immune response and a systemic inflammatory response develop after allogeneic BMT. Because type 2 cytokines can inhibit the production of the proinflammatory cytokines interleukin-1 and tumor necrosis factor-alpha, a type 1 to type 2 shift in the initial response of donor T cells to host alloantigens may interrupt the cytokine cascade after allogeneic BMT and may offer a new approach to the prevention and treatment of acute GVHD. Interventions to specifically eliminate or modify the response of donor T cells to alloantigens in order to reduce GVHD may obviate the need for T cell depletion in clinical BMT and thus avoid the increased risk of relapse of malignancy and impairment of donor cell engraftment.
177 citations
TL;DR: It appears that cytokines favoring the maintenance of fetal survival mainly belong to the Th2 pathway, whereas the failure of pregnancy rather associates with the predominance of Th1- type cytokines and/or the absence of Th2-type cytokines.
Abstract: There is clear evidence to suggest that the maternal immune system during pregnancy can enhance or inhibit the development of the fetoplacental unit Recent data support the view that some cytokines produced by both T cells and non-T cells (IL-3, GM-CSF, TGF-beta, IL-4, IL-10), favor fetal survival and growth In contrast, other cytokines, such as IFN-gamma, TNF-beta and TNF-alpha, can rather compromise pregnancy Accordingly, we show here that T-cell clones generated from the decidua of women with unexplained recurrent abortion produced significantly lower concentrations of IL-4 than clones derived from the decidua of voluntary abortions or the endometrium of nonpregnant women Thus, despite the complexity of the cytokine network, it appears that cytokines favoring the maintenance of fetal survival mainly belong to the Th2 pathway, whereas the failure of pregnancy rather associates with the predominance of Th1-type cytokines and/or the absence of Th2-type cytokines Interestingly, we also found that, at least in vitro, progesterone promotes the preferential development of Th2-like cells and induces transient IL-4 production by established Th1 cells, whereas relaxin, another corpus luteum-derived hormone, mainly promotes the development of Th1-like cells These data provide an excellent basis for investigating the relationship between the endocrine and the immune system in the regulation of the maternal-fetal interaction
149 citations
TL;DR: It is suggested that this imbalanced cytokine production may well account for the pattern of immune response which may be observed in the elderly, i.e. a normal or increased humoral response in face of a low T cell immune responsiveness.
Abstract: It is well known that aging is associated with various alterations in lymphoid cell functions, particularly with a progressive decline in immune responsiveness to exogenous antigens and increasing incidence of autoimmune phenomena. Many studies have been focused on the mechanisms of the immunologic features of aging. this review describes our results of studies performed to determine the influence of age on the capacity to produce interleukin-2 (IL-2), interferon-gamma (IFN-gamma), interleukin-4 (IL-4), interleukin-t (IL-5), interleukin-6 (IL-6) and tumor necrosis factor (TNF). Mitogen-stimulated cultures of mononuclear cells (MNC) from human beings were assessed for cytokine-producing capacity. A significant decrease in IFN-gamma and IL-2 production by MNC cultures from elderly individuals was observed. No significant difference was instead observed between cultures from elderly individuals and those from young ones as regards TNF-alpha, IL-4 and IL-6 production. Mitogen or antigen-stimulated cultures of MNC from aged mice also displayed a significant decrease in IFN-gamma and IL-2 production as well as TNF-beta. Instead IL-4 and IL-5 production significantly increased in these cultures. We suggest that this imbalanced cytokine production may well account for the pattern of immune response which may be observed in the elderly, i.e. a normal or increased humoral response (including autoimmune responses) in face of a low T cell immune responsiveness.
132 citations
TL;DR: Activation of integrin-mediated intracellular signals may promote inflammation by facilitating leukocyte recruitment and cytokine expression.
Abstract: Lung injury triggers an acute inflammatory response characterized by increased expression and deposition of extracellular matrix (ECM) components such as fibronectin and collagen. Although the function of newly deposited matrices in injured lungs is unknown, their ability to affect the migration, proliferation, differentiation, and activation state of cells in vitro suggests an important role in the initiation and maintenance of the inflammatory response in vivo. Interactions between immune and nonimmune cells with the lung ECM are mediated via cell surface receptors of the integrin family which link the ECM with intracellular molecules involved in signal transduction. Activation of integrin-mediated intracellular signals may promote inflammation by facilitating leukocyte recruitment and cytokine expression. *** DIRECT SUPPORT *** A02GS030 00009
75 citations
TL;DR: It is found that decreased LFA-1 and VLA-4 on peripheral blood leukocytes in SCI patients and lower levels of CAMs in SCT patients with pressure ulcers than in those without them.
Abstract: Multiple communicative pathways among the nervous, endocrine and immune systems facilitate physiological immunoregulation. Spinal cord injury (SCI) patients have decreased natural (NK cell) and adaptive (T cell) immune function and reduced blood levels of cellular adhesion molecules (CAMs) that participate in immune function and wound healing. We found decreased LFA-1 and VLA-4 on peripheral blood leukocytes in SCI patients and lower levels of CAMs in SCT patients with pressure ulcers than in those without them. SCI might affect immune cells and immune responsiveness by: (1) disrupting the outflow of signals from the sympathetic nervous system to lymphoid tissues and their blood vessels as well as the returning afferent signals from these tissues to the brain; (2) immunosuppression caused by the stressors affecting SCI patients; (3) interrupting returning signals to the CNS from the periphery thereby reducing facilitation of immunoregulatory CNS neurons and decreasing their activity; or a combination of all three. SCI patients may develop dysregulation of the sympathetic nervous system that is intimately involved in immune function. Chronic stress mediates immunosuppression by corticosteroids, catecholamines, endorphins and met-enkephalin. The hypothalamus coordinates the response to stress through the release of soluble products from the sympathetic nervous system and hypothalamic-pituitary-adrenal axis. Whereas the nervous and endocrine systems are not concerned with immunological specificity, they do influence the intensity, kinetics and localization of immune responses. Products of an activated immune system may generate feedback circuits capable of inhibiting, enhancing or regulating neuronal input. Immune system cells can produce neurologically active peptides including ACTH, CRF, growth hormone, thyrotropin, prolactin, human chorionic gonadotropin, endorphin, enkephalins, substance P, somatostatin and VIP. Cytokines are likely important mediators of the HPA response to immune stimuli.
62 citations
TL;DR: The nature of the antitumor immune response to human melanoma has been revealed at a molecular level and has implications not only for understanding of theimmune response to self peptides in normal and pathologic conditions, but also for the development of immunotherapies for cancer and autoimmune diseases.
Abstract: Human melanoma antigens and their epitopes recognized by T cells have recently been identified. HLA-A2 binding epitopes of melanoma antigens MART-1 and gp100 were characterized and suspected to be subdominant/cryptic self determinants. Together with other findings of tumor-specific mutated self peptides as tumor antigens recognized by T cells, the nature of the antitumor immune response to human melanoma has been revealed at a molecular level. These findings have implications not only for understanding of the immune response to self peptides in normal and pathologic conditions, but also for the development of immunotherapies for cancer and autoimmune diseases.
59 citations
TL;DR: In vitro and in vivo studies have provided promising preliminary results suggesting that, at at certain stages of disease, the benefits of IL-2-mediated immune enhancement may outweigh or override the inductive effects of this cytokine on HIV production.
Abstract: A hallmark of human immunodeficiency virus (HIV) infection is the progressive loss of CD4+ T lymphocytes; however, qualitative defects in immune responses occur prior to the precipitous drop CD4+ T cell numbers. One of the first immunologic defects to be described in HIV-infected individuals is a deficiency in interleukin (IL)-2 production. The addition of IL-2 in vitro to cultures of mononuclear cells from HIV-infected individuals partially or completely restored certain defective cellular immune responses. However, production of or addition of IL-2 has also been associated with increased viral replication in infected T cells. These observations underscore the pernicious correlation between immune activation and HIV replication. However, recent in vitro and in vivo studies have provided promising preliminary results suggesting that, at least at certain stages of disease, the benefits of IL-2-mediated immune enhancement may outweigh or override the inductive effects of this cytokine on HIV production.
44 citations
TL;DR: The current paper reviews the data regarding the involvement of the immune system in atherogenesis with respect to the antigenic candidates mentioned above and two major antigenic determinants against which the immune response may be triggered.
Abstract: Atherosclerosis is a histopathological process of a multifactorial orgin. Whereas the genetic and biochemical causes received considerable attention, the involvement of the immune system has generally been considered negligible. In recent years evidence has been presented to support the dominant role played by the immune system in atherosclerosis. Two major antigenic determinants against which the immune response may be triggered have been suggested, namely the heat shock protein 60/65 and oxidized low density lipoprotein. The current paper reviews the data regarding the involvement of the immune system in atherogenesis with respect to the antigenic candidates mentioned above.
35 citations
TL;DR: Observations about CD4+ T-cell-induced, Fas-mediated B cell death in the context of other factors that affect apoptosis in B cells, normal and malignant are considered.
Abstract: Mechanisms of B cell apoptosis are critical in reducing aberrant B cell proliferations such as those that arise in autoimmune disease and in B cell malignancies. The physiologic interaction of CD4+ helper T cells and B lymphocytes has been extensively studied over the past two decades. Although CD4+ T cells are considered primarily to offer positive costimulatory signals for B cell differentiation into active immunoglobulin-secreting cells, recent studies have shown that CD4+ T cells are crucial in downregulating the humoral immune response. In the course of cognate interaction between CD40 ligand (CD40L)-bearing CD4+ T cells and CD40-expressing germinal center B cells, CD40 ligation results in augmented Fas expression at the B cell surface. Like CD40L, Fas ligand is expressed on activated CD4+ Th1 cells and when bound to Fas receptor on the B cell surface, initiates an apoptotic signal in that cell. Thus, CD4+ T cells limit the growth of autologous germinal center B cells by first inducing Fas expression and then instigating a death signal via Fas ligand. In this work, we will consider these observations about CD4+ T-cell-induced, Fas-mediated B cell death in the context of other factors that affect apoptosis in B cells, normal and malignant.
34 citations
TL;DR: In vitro and in vivo studies with CTLA4Ig demonstrate that it is an extremely effective immunosuppressive agent in models of transplantation and autoimmunity and Mechanistic studies indicate that CTLA 4Ig may work by partially inhibiting the expansion of antigen-reactive cells and inducing anergy in the residual population.
Abstract: It is now well established that T cells require two signals for activation and effector function. The first signal is provided through the T cell receptor for antigen. The best-characterized pathway which provides the second, or costimulatory, signal is through the CD28 receptor on the surface of T cells. In vitro, ligation of the T cell receptor without a second signal induces a long-lived state of anergy in T cells. CD28 has two known ligands, B7-1 and B7-2, expressed on activated antigen-presenting cells. A soluble fusion protein called CTLA4Ig has been produced which binds B7-1 and B7-2 and acts as a competitive inhibitor of CD28. In vitro and in vivo studies with CTLA4Ig demonstrate that it is an extremely effective immunosuppressive agent in models of transplantation and autoimmunity. Mechanistic studies indicate that CTLA4Ig may work by partially inhibiting the expansion of antigen-reactive cells and inducing anergy in the residual population.
33 citations
TL;DR: Inhibition studies indicate that specific tyrosine phosphorylation following PTK activation is involved in the mobilization of the transcription factor, nuclear factor κB, and VCAM-1 mRNA expression, which may have implications for pathophysiological conditions that involve the upregulation of these molecules.
Abstract: Induction of endothelial adhesion molecules by the cytokine tumor necrosis factor-α (TNF) can occur independently of protein kinase C and activation of a protein tyrosine kinase (PTK) has recently been implicated in the upregulation of vascular cell adhesion molecule 1 (VCAM-1) by interleukin-4 (IL-4) on endothelial cells. We demonstrate that the PTK inhibitors herbimycin A or genistein suppress induction of endothelial VCAM-1 and E-selectin, as well as subsequent monocytic cell adhesion to endothelial cells stimulated by TNF. Inhibition studies indicate that specific tyrosine phosphorylation following PTK activation is involved in the mobilization of the transcription factor, nuclear factor κB, and VCAM-1 mRNA expression. This may have implications for pathophysiological conditions that involve the upregulation of these molecules (e.g. inflammation and atherosclerosis).
TL;DR: The available data provide explanations for why only APC which express high levels of multiple costimulatory/adhesion molecules, such as dendritic cells and activated B cells, induce efficient naive T cell responses, and suggest that ICAM-1/LFA-1 and B7/CD28 interactions are major pathways used to initiate naive CD4 activation.
Abstract: Naive CD4 T cell activation is a complex process involving many steps. T cell receptor (TCR) signals, provided by interaction with peptide/MHC on antigen-presenting cells (APC), control many events associated with activation. The extent of TCR signaling and the magnitude of the T cell response is in turn controlled by accessory molecules on APC, which stabilize T-APC interactions. Full T cell activation additionally requires multiple costimulatory signals, generated upon ligation of T cell coreceptors by accessory molecules, and these lead to IL-2 production, proliferation and differentiation of the naive cell into an effector state. This review summarizes the role played by accessory molecules in naive CD4 activation and discusses how integration of signals from these molecules, with signals from the TCR, may determine the outcome of T-APC interaction. The available data provide explanations for why only APC which express high levels of multiple costimulatory/adhesion molecules, such as dendritic cells and activated B cells, induce efficient naive T cell responses, and suggest that ICAM-1/LFA-1 and B7/CD28 interactions are major pathways used to initiate naive T cell activation.
TL;DR: A subunit malaria vaccine that includes CD8+ T cell epitopes restricted by the most common class I HLA alleles, including HLA-A2, can now be constructed using a combination of immunochemical and cellular immunologic analyses.
Abstract: In animal models, CD8+ T cells are a critical effector mechanism in the protective immunity against malaria. Conventional approaches to the development of many vaccines, including those against malaria, have however proved inadequate. In particular, an alternative approach is needed for the development of vaccines designed to induce a cellular immune response mediated by CD8+ T cells. Advances in the field of molecular immunology during the past decade have provided an insight into the presentation of peptides by MHC class I molecules and their recognition by CD8+ T cells. These studies have provided a conceptual basis for the development of efficacious parasitic and viral vaccines. By a combination of immunochemical and cellular immunologic analyses based on specific peptide binding motifs, a subunit malaria vaccine that includes CD8+ T cell epitopes restricted by the most common class I HLA alleles, including HLA-A2, can now be constructed.
TL;DR: In this paper, the TCR α-chain and polymorphic residues of the major histocompatibility complex (MHC) were found to play a role in superantigen recognition.
Abstract: Superantigens bind to antigen-presenting cells on the outside of the major histocompatibility complex (MHC) class II molecule and to T cells via the external face of the T cell receptor (TCR) Vβ element. As a consequence, superantigens stimulate populations of T cells in a Vβ-specific, non-MHC-restricted manner. However, accumulating evidence has shown an additional contribution of the TCR α-chain and polymorphic residues of the MHC molecule to superantigen recognition by some T cells. These data suggest that the TCR and MHC come into contact during superantigen engagement and indirectly modulate the superantigen reactivity. Thus, additional interactions between non-Vβ elements of the TCR and MHC play a role in the overall stability of the superantigen/MHC/TCR complex, explaining the influence of the TCR α-chain. It is likely that this additional interaction is of greater consequence for weakly reactive T cells. This modulation of superantigen reactivity in individual T cells may have physiological consequences, for example, in the induction of autoimmunity.
TL;DR: The recent development of an assay measuring substrate binding to the TAP complex has led to the identification of the major structural properties of peptides selected by the human transporter.
Abstract: Peptide epitopes presented by HLA class I are supplied by an elaborate system of antigen processing which subjects candidate epitopes to a process of selection according to little-understood rules. Transport of peptides from the cytosol into the endoplasmic reticulum by the TAP (transporter associated with antigen processing) complex is likely to play an important role in peptide selection for presentation. The recent development of an assay measuring substrate binding to the TAP complex has led to the identification of the major structural properties of peptides selected by the human transporter. Human TAP favors transport of peptides with structural features common to HLA class I ligands. However, TAP dislikes peptide ligands preferred by some HLA class I alleles, which may therefore frequently rely on alternative sources of peptide ligands.
TL;DR: Whether the type of antigen-presenting cells (APCs) and the distinct expression of important adhesion molecules like CD80 and CD86 may influence the generation of CD4+ CTLs is discussed here.
Abstract: CD4+ T cells can exert different effector functions, which are partly distinguishable by the secretion of different cytokines, namely by either IFN-γ, IL-2 and lymphotoxins for Th1-like or IL-4, IL-5, IL-10 and IL-13 for Th2-like T cells. Th1-like T cells can exert cytotoxic functions, too. The cytokinetic phenotype of an activated T cell clone (TCC) is mainly influenced by the cytokinetic pattern of the microenvironment where it was activated. However, the interaction between certain adhesion molecules (i.e. CD28-CD80 and CD28-CD86) may also have an influence on the functionality of the reactive T cell. On the contrary, the requirements for the induction of CD4+ cytotoxic T cells (CD4+CTLs) are not well understood. We have focused this review on studies investigating the development of CD4+ T cells with cytotoxic effector functions. In particular, we discuss here whether the type of antigen-presenting cells (APCs) and the distinct expression of important adhesion molecules like CD80 and CD86 may influence the generation of CD4+ CTLs. Among a large panel of APCs only dendritic cells and TCCs are able to induce cytotoxicity. The level of CD80, but not of CD86, present on the APCs appears to be crucial for the induction of CD4+ CTLs.
TL;DR: The identification of a highly enriched bone marrow population capable of repopulating recipient mice with mature NK cells and the findings and those of others are summarized in an attempt to clarify the current status of murine natural killer cell differentiation.
Abstract: Natural killer cells are bone marrow-derived lymphocytes capable of lysing a variety of target cells without prior exposure. While the biological activities and function of mature NK cells have been extensively investigated, the differentiation of NK cells from primitive hematopoietic stem cells is poorly understood. Recently, we have reported on the identification of a highly enriched bone marrow population capable of repopulating recipient mice with mature NK cells. In this review, we will summarize our findings and those of others in an attempt to clarify the current status of murine natural killer cell differentiation.
TL;DR: The transporter associated with antigen processing selectively translocates cytoplasmically derived peptides of appropriate sequence and length into the lumen of the endoplasmic reticulum where they associate with newly synthesized class I molecules.
Abstract: The presentation of antigenic peptides by class I major histocompatibility complex molecules plays a central role in the cellular immune response, since immune surveillance for detection of viral infections or malignant transformations is achieved by CD8+ T lymphocytes which inspect peptides, derived from intracellular proteins, bind to class I molecules on the surface of most cells. The transporter associated with antigen processing selectively translocates cytoplasmically derived peptides of appropriate sequence and length into the lumen of the endoplasmic reticulum where they associate with newly synthesized class I molecules. The translocated peptides are generated by multicatalytic and multisubunit proteasomes which degrade cytoplasmic proteins in a ATP-ubiquitin-dependent manner. This review discusses our current molecular understanding of class I antigen processing and presentation.
TL;DR: The authors' studies of γ/δ T cells, expressing the β3 integrin vitronectin receptor (VNR), reflect some of the consequences this active interaction between lymphocytes and the ECM could have for T cell activation and differentiation.
Abstract: Integrins are a family of cell surface receptors which mediate the adhesion of cells to each other or to extracellular matrix (ECM) proteins. The interaction of integrins with their ligands or counter-receptors was initially considered to be a one-way process in that cells actively regulate the interaction of integrins with their ligands ('inside-out signal'). In contrast, it was not obvious that cells would receive a signal from the outside via the integrin heterodimers following ligand binding ('outside-in signal'). Recent evidence increasingly supports the active role of integrins in cell activation and proliferation. Many reports describe the effects of integrin-mediated signaling in lymphoid cells. Our studies of gamma/delta T cells, expressing the beta 3 integrin vitronectin receptor (VNR), reflect some of the consequences this active interaction between lymphocytes and the ECM could have for T cell activation and differentiation. The VNR has been described as a T cell costimulatory molecule. We recently reported that the VNR has the potential to stimulate cytokine secretion in T cell hybridomas without involvement of T cell receptor-mediated signals. Further studies demonstrated tyrosine phosphorylation of proteins following VNR cross-linking and the interaction of the VNR with protein kinases. Intensive research focuses on the signal transduction mechanisms of integrins and their interaction with other costimulatory or activation molecules. This knowledge is important to better understand the role of adhesion molecules, the ECM, and the cellular microenvironment for lymphocyte activation and differentiation.
TL;DR: These antigens may have a role in the pathogenesis of uveitis in a subset of patients with JCA, and are suggested to be related to peptide M and R16 of interphotoreceptor retinoid binding protein.
Abstract: The objective of this study was to determine the proliferative responses of peripheral blood lymphocytes of ocular antigens like retinal S-antigen, peptides M and G of S-antigen, yeast histone H3 peptide 106–121 homologous to peptide M and peptide R16 of interphotoreceptor retinoid binding protein (IRBP) in children with juvenile chronic arthritis (JCA). We have studied the in vitro proliferative response of peripheral blood lymphocytes from 41 patients with JCA (10 with and 31 without uveitis) and 23 healthy controls against the above antigens. The responders were retested after 1 or 6 months. Fifty (5/10) and 9.7% (3/31) of JCA patients with and without uveitis, respectively, responded (stimulation index >3) to S-antigen or one of its peptide listed above or yeast histone H3 peptide or R16 of IRBP. None of the healthy controls responded to any of these antigens. The difference in the frequency of responders (SI>3) between JCA associated with uveitis and healthy controls was statistically significant (p=0.001). Similarly, the difference between JCA with and without uveitis was also significant (p=0.013). Our findings suggest that these antigens may have a role in the pathogenesis of uveitis in a subset of patients with JCA.
TL;DR: Investigation of the involvement of 65-kDa HSP (HSP65) in host protection against an intracellular protozoan parasite, Toxoplasma gondii, in mice revealed that induction of murine HSP65 on macrophages closely correlates with protection against infection with this protozoa.
Abstract: Heat shock proteins (HSPs) are evolutionarily highly conserved polypeptides synthesized by many cells to preserve cellular functions under a variety of stressful conditions including infections. We have investigated the involvement of 65-kDa HSP (HSP65) in host protection against an intracellular protozoan parasite,Toxoplasma gondii, in mice. Experiments using low and highly virulent strains ofTox. gondii revealed that induction of murine HSP65 on macrophages closely correlates with protection against infection with this protozoan. Furthermore, we clarified that T cells, especially γδ T cells, are indispensable for HSP65 expression. A similar relationship between the expression of HSP65 on host macrophages and protective immunity was observed in mice infected withLeishmania major andTrypanosoma cruzi, both of which are obligate intracellular protozoa as isTox. gondii.
TL;DR: Molecular mimicry and the mechanism of induction of oral tolerance with respect to immunopathogenesis of T-cell-mediated autoimmune diseases in general and EAU in particular are discussed.
Abstract: Intraocular inflammatory disease or uveitis, which affects the uveal tract and the retina of the eyes in human, is the major cause of visual impairment. Experimental autoimmune uveitis (EAU) is a T-cell-mediated autoimmune disease directed against retinal proteins and has been studied in several mammalian species including subhuman primates as a model for human posterior uveitis. Autoimmune responses provoked by molecular mimicry occur when the nonself and host determinants are similar enough to cross-react yet different enough to break immunological tolerance, and is one of the proposed mechanisms for induction of autoimmune diseases. Therapeutic immunomodulatory strategies have been used to induce antigen-specific peripheral immune tolerance in animal models of T-cell-mediated autoimmune diseases by oral administration of autoantigens. Oral tolerance leads to unique mechanisms of tissue and disease-specific immunosuppression, which would circumvent the immunotherapeutic problem of multiple target tissue autoreactivity. Several groups have investigated the effects of delivering autoantigens across gastric mucosal surfaces. This review briefly discusses molecular mimicry and the mechanism of induction of oral tolerance with respect to immunopathogenesis of T-cell-mediated autoimmune diseases in general and EAU in particular.
TL;DR: The mechanisms by which the hierarchy of determinants on a self protein can be disrupted, thereby leading to the presentation of previously cryptic self peptides and the induction of an autoimmune T-cell-mediated process are analyzed.
Abstract: Autologous proteins are continuously processed and presented in the form of peptides associated with self major histocompatibility (MHC) molecules at the surface of antigen-presenting cells for interaction with autoreactive T cells. During thymic selection, the presentation of self peptides is an essential element in the establishment of the T cell repertoire. Developing T cells which recognize self peptide/self MHC complexes with sufficient affinity are clonally deleted. However, we and others have recently demonstrated that a variety of self peptides, despite their high binding affinity to MHC molecules, never reach the threshold of presentation to ensure negative selection (cryptic self peptides). This mechanism may have been selected to avoid excessive purging of T cell repertoire during ontogeny. However, T cells directed to cryptic self determinants represent a continuous threat for the initiation of autoimmunity in adults. Supporting this view, recent studies have documented the involvement of cryptic self peptide presentation in different autoimmune diseases. In this article, we examine the factors that govern the selection of self peptides for presentation to autoreactive T cells in vivo and discuss their contribution to both the induction and the maintenance of self tolerance. In addition, we analyze the mechanisms by which the hierarchy of determinants on a self protein can be disrupted, thereby leading to the presentation of previously cryptic self peptides and the induction of an autoimmune T-cell-mediated process.
TL;DR: Current in vitro systems to study the differences in BCR-mediated signal transduction in immature and mature B lymphocytes are discussed and previously published work is discussed in order to illustrate how these model systems have been useful in beginning to unravel the molecular basis for immune B cell negative selection and tolerance.
Abstract: Encounter with antigen by newly developing antigen receptor-positive B cells leads to negative selection. This process positions the B cell antigen receptor (BCR) in a central role for initiating the process of negative selection and suggests developmental regulation of its signaling. The observation that immature B cells are more susceptible to negative selection than are mature B cells has been demonstrated in a number of in vitro and in vivo model systems and support the idea of developmental regulation of BCR-initiated responses. Since identical antigen receptors are expressed on immature and mature B cells, the critical fate-determining distinction between these developmental stages must lie downstream of the receptor-ligand interaction itself, in the form of different BCR-linked signaling processes or with different secondary events occurring subsequent to BCR cross-linking. To address the first possibility, our laboratory and others have sought to define the differences in BCR-mediated signal transduction in immature and mature B lymphocytes. In this review article we will discuss current in vitro systems to study this question in primary, nontransformed murine B lymphocytes. In addition, we will discuss our previously published work in order to illustrate how these model systems have been useful in beginning to unravel the molecular basis for immune B cell negative selection and tolerance.
TL;DR: Human cytolytic T lymphocytes specific for autologous Burkitt's lymphoma express the γ,δ T cell receptor and recognize immunoglobulin idiotype in an MHC-unrestricted manner, implicating these molecules in tumor recognition and antigen presentation.
Abstract: Human cytolytic T lymphocytes specific for autologous Burkitt's lymphoma express the γ,δ T cell receptor and recognize immunoglobulin idiotype in an MHC-unrestricted manner. Antibodies against a member of the heat shock protein 70 family inhibit this specific cytotoxicity, implicating these molecules in tumor recognition and antigen presentation. Such data is relevant to the design of novel immunotherapies for cancer and provides new insights into target recognition by γ,δ T cells.