Showing papers on "Antigen published in 2005"
TL;DR: This Review article focuses on the relevance of L-arginine metabolism by myeloid cells for immunity under physiological and pathological conditions.
Abstract: L-Arginine is an essential amino acid for birds and young mammals, and it is a conditionally essential amino acid for adult mammals, as it is important in situations in which requirements exceed production, such as pregnancy. Recent findings indicate that increased metabolism of L-arginine by myeloid cells can result in the impairment of lymphocyte responses to antigen during immune responses and tumour growth. Two enzymes that compete for L-arginine as a substrate - arginase and nitric-oxide synthase - are crucial components of this lymphocyte-suppression pathway, and the metabolic products of these enzymes are important moderators of T-cell function. This Review article focuses on the relevance of L-arginine metabolism by myeloid cells for immunity under physiological and pathological conditions.
1,564 citations
TL;DR: The conversion of truly naive CD4+ T cells into suppressor cells expressing Foxp3 is reported by targeting of peptide-agonist ligands to dendritic cells and by analysis of Foxp 3 expression at the level of single cells, showing that conversion was achieved by minute antigen doses with suboptimal dendrite cell activation.
Abstract: Evidence suggests that regulatory T cells expressing the transcription factor Foxp3 develop extrathymically and intrathymically. Mechanisms of extrathymic induction require further scrutiny, especially as proliferation and/or phenotypic changes of preexisting suppressor cells must be distinguished from true de novo generation. Here we report the conversion of truly naive CD4+ T cells into suppressor cells expressing Foxp3 by targeting of peptide-agonist ligands to dendritic cells and by analysis of Foxp3 expression at the level of single cells. We show that conversion was achieved by minute antigen doses with suboptimal dendritic cell activation. The addition of transforming growth factor-β or the absence of interleukin 2 production, which reduces proliferation, enhanced the conversion rate. In addition, regulatory T cell populations induced in subimmunogenic conditions could subsequently be expanded by delivery of antigen in immunogenic conditions. The extrathymic generation and proliferation of regulatory T cells may contribute to self-tolerance as well as the poor immunogenicity of tumors and may be exploited clinically to prevent or reverse unwanted immunity.
1,291 citations
TL;DR: The immunogenicity of antigens delivered by dendritic cells has now been shown in patients with cancer, and a better understanding of how dendrites regulate immune responses will allow us to better exploit these cells to induce effective antitumour immunity.
Abstract: Mouse studies have shown that the immune system can reject tumours, and the identification of tumour antigens that can be recognized by human T cells has facilitated the development of immunotherapy protocols. Vaccines against cancer aim to induce tumour-specific effector T cells that can reduce the tumour mass, as well as tumour-specific memory T cells that can control tumour relapse. Owing to their capacity to regulate T-cell immunity, dendritic cells are increasingly used as adjuvants for vaccination, and the immunogenicity of antigens delivered by dendritic cells has now been shown in patients with cancer. A better understanding of how dendritic cells regulate immune responses will allow us to better exploit these cells to induce effective antitumour immunity.
1,221 citations
TL;DR: There is an urgent need to establish standard panels of HIV-1 reference strains for wide distribution and a lack of uniformity in target strains used by different investigators to assess cross-neutralization has made the comparison of vaccine-induced antibody responses difficult.
Abstract: Induction of broadly cross-reactive neutralizing antibodies is a high priority for AIDS vaccine development but one that has proven difficult to be achieved. While most immunogens generate antibodies that neutralize a subset of T-cell-line-adapted strains of human immunodeficiency virus type 1 (HIV-1), none so far have generated a potent, broadly cross-reactive response against primary isolates of the virus. Even small increments in immunogen improvement leading to increases in neutralizing antibody titers and cross-neutralizing activity would accelerate vaccine development; however, a lack of uniformity in target strains used by different investigators to assess cross-neutralization has made the comparison of vaccine-induced antibody responses difficult. Thus, there is an urgent need to establish standard panels of HIV-1 reference strains for wide distribution. To facilitate this, full-length gp160 genes were cloned from acute and early subtype B infections and characterized for use as reference reagents to assess neutralizing antibodies against clade B HIV-1. Individual gp160 clones were screened for infectivity as Env-pseudotyped viruses in a luciferase reporter gene assay in JC53-BL (TZM-bl) cells. Functional env clones were sequenced and their neutralization phenotypes characterized by using soluble CD4, monoclonal antibodies, and serum samples from infected individuals and noninfected recipients of a recombinant gp120 vaccine. Env clones from 12 R5 primary HIV-1 isolates were selected that were not unusually sensitive or resistant to neutralization and comprised a wide spectrum of genetic, antigenic, and geographic diversity. These reference reagents will facilitate proficiency testing and other validation efforts aimed at improving assay performance across laboratories and can be used for standardized assessments of vaccine-elicited neutralizing antibodies.
1,127 citations
TL;DR: This review concentrates on the properties of antigen-presenting cells, especially those aspects of their overall organization, regulation, and intracellular transport that both facilitate and modulate the processing of protein antigens.
Abstract: The conversion of exogenous and endogenous proteins into immunogenic peptides recognized by T lymphocytes involves a series of proteolytic and other enzymatic events culminating in the formation of peptides bound to MHC class I or class II molecules. Although the biochemistry of these events has been studied in detail, only in the past few years has similar information begun to emerge describing the cellular context in which these events take place. This review thus concentrates on the properties of antigen-presenting cells, especially those aspects of their overall organization, regulation, and intracellular transport that both facilitate and modulate the processing of protein antigens. Emphasis is placed on dendritic cells and the specializations that help account for their marked efficiency at antigen processing and presentation both in vitro and, importantly, in vivo. How dendritic cells handle antigens is likely to be as important a determinant of immunogenicity and tolerance as is the nature of the antigens themselves.
1,126 citations
TL;DR: Evidence is reported for microbial, antigen-specific activation of NKT cells against Gram-negative, lipopolysaccharide (LPS)-negative alpha-Proteobacteria such as Ehrlichia muris and Sphingomonas capsulata and shows that glycosylceramides are an alternative to LPS for innate recognition of the Gram- negative, LPS-negative bacterial cell wall.
Abstract: CD1d-restricted natural killer T (NKT) cells are innate-like lymphocytes that express a conserved T-cell receptor and contribute to host defence against various microbial pathogens. However, their target lipid antigens have remained elusive. Here we report evidence for microbial, antigen-specific activation of NKT cells against Gram-negative, lipopolysaccharide (LPS)-negative alpha-Proteobacteria such as Ehrlichia muris and Sphingomonas capsulata. We have identified glycosylceramides from the cell wall of Sphingomonas that serve as direct targets for mouse and human NKT cells, controlling both septic shock reaction and bacterial clearance in infected mice. In contrast, Gram-negative, LPS-positive Salmonella typhimurium activates NKT cells through the recognition of an endogenous lysosomal glycosphingolipid, iGb3, presented by LPS-activated dendritic cells. These findings identify two novel antigenic targets of NKT cells in antimicrobial defence, and show that glycosylceramides are an alternative to LPS for innate recognition of the Gram-negative, LPS-negative bacterial cell wall.
1,108 citations
TL;DR: Gaining a better understanding of the crosstalk between dendritic cells and lymphatic vessels during the migration of d endritic cells to lymph nodes is essential for future advances in manipulating dendrite-cell migration as a means to fine-tune immune responses in clinical settings.
Abstract: Antigen-presenting dendritic cells often acquire foreign antigens in peripheral tissues such as the skin. Optimal encounter with naive T cells for the presentation of these antigens requires that the dendritic cells migrate to draining lymph nodes through lymphatic vessels. In this article, we review important aspects of what is known about dendritic-cell trafficking into and through lymphatic vessels to lymph nodes. We present these findings in the context of information about lymphatic-vessel biology. Gaining a better understanding of the crosstalk between dendritic cells and lymphatic vessels during the migration of dendritic cells to lymph nodes is essential for future advances in manipulating dendritic-cell migration as a means to fine-tune immune responses in clinical settings.
1,082 citations
TL;DR: The first exosome Phase I trial highlighted the feasibility of large scale exosomal MHC class II molecules production and the safety of exosomes administration.
Abstract: BACKGROUND: DC derived-exosomes are nanomeric vesicles harboring functional MHC/peptide complexes capable of promoting T cell immune responses and tumor rejection Here we report the feasability and safety of the first Phase I clinical trial using autologous exosomes pulsed with MAGE 3 peptides for the immunization of stage III/IV melanoma patients Secondary endpoints were the monitoring of T cell responses and the clinical outcome PATIENTS AND METHODS: Exosomes were purified from day 7 autologous monocyte derived-DC cultures Fifteen patients fullfilling the inclusion criteria (stage IIIB and IV, HLA-A1+, or -B35+ and HLA-DPO4+ leukocyte phenotype, tumor expressing MAGE3 antigen) were enrolled from 2000 to 2002 and received four exosome vaccinations Two dose levels of either MHC class II molecules (013 versus 040 x 1014 molecules) or peptides (10 versus 100 mug/ml) were tested Evaluations were performed before and 2 weeks after immunization A continuation treatment was performed in 4 cases of non progression RESULTS: The GMP process allowed to harvest about 5 x 1014 exosomal MHC class II molecules allowing inclusion of all 15 patients There was no grade II toxicity and the maximal tolerated dose was not achieved One patient exhibited a partial response according to the RECIST criteria This HLA-B35+/A2+ patient vaccinated with A1/B35 defined CTL epitopes developed halo of depigmentation around naevi, a MART1-specific HLA-A2 restricted T cell response in the tumor bed associated with progressive loss of HLA-A2 and HLA-BC molecules on tumor cells during therapy with exosomes In addition, one minor, two stable and one mixed responses were observed in skin and lymph node sites MAGE3 specific CD4+ and CD8+ T cell responses could not be detected in peripheral blood CONCLUSION: The first exosome Phase I trial highlighted the feasibility of large scale exosome production and the safety of exosome administration
1,029 citations
TL;DR: The activation of NKT cells paradoxically can lead either to suppression or stimulation of immune responses, and one cannot predict which will occur, and many investigators are hopeful that immune therapies can be developed based on NKT cell stimulation.
Abstract: Natural killer T (NKT) cells constitute a conserved T cell sublineage with unique properties, including reactivity for a synthetic glycolipid presented by CD1d, expression of an invariant T cell antigen receptor (TCR) alpha chain, and unusual requirements for thymic selection. They rapidly produce many cytokines after stimulation and thus influence diverse immune responses and pathogenic processes. Because of intensive research effort, we have learned much about factors promoting the development and survival of NKT cells, regulation of their cytokine production, and the means by which they influence dendritic cells and other cell types. Despite this progress, knowledge of the natural antigen(s) they recognize and their physiologic role remain incomplete. The activation of NKT cells paradoxically can lead either to suppression or stimulation of immune responses, and we cannot predict which will occur. Despite this uncertainty, many investigators are hopeful that immune therapies can be developed based on NKT cell stimulation.
1,014 citations
TL;DR: It is shown that peak virus production in gut tissues of SIV-infected rhesus macaques coincides with peak numbers of infected memory CD4+ T cells, underscoring the importance of developing countermeasures to SIV that are effective before infection of GALT.
Abstract: In early simian immunodeficiency virus (SIV) and human immunodeficiency virus-1 (HIV-1) infections, gut-associated lymphatic tissue (GALT), the largest component of the lymphoid organ system, is a principal site of both virus production and depletion of primarily lamina propria memory CD4+ T cells; that is, CD4-expressing T cells that previously encountered antigens and microbes and homed to the lamina propria of GALT. Here, we show that peak virus production in gut tissues of SIV-infected rhesus macaques coincides with peak numbers of infected memory CD4+ T cells. Surprisingly, most of the initially infected memory cells were not, as expected, activated but were instead immunophenotypically 'resting' cells that, unlike truly resting cells, but like the first cells mainly infected at other mucosal sites and peripheral lymph nodes, are capable of supporting virus production. In addition to inducing immune activation and thereby providing activated CD4+ T-cell targets to sustain infection, virus production also triggered an immunopathologically limiting Fas-Fas-ligand-mediated apoptotic pathway in lamina propria CD4+ T cells, resulting in their preferential ablation. Thus, SIV exploits a large, resident population of resting memory CD4+ T cells in GALT to produce peak levels of virus that directly (through lytic infection) and indirectly (through apoptosis of infected and uninfected cells) deplete CD4+ T cells in the effector arm of GALT. The scale of this CD4+ T-cell depletion has adverse effects on the immune system of the host, underscoring the importance of developing countermeasures to SIV that are effective before infection of GALT.
970 citations
TL;DR: Principal advances in the understanding of the molecular mechanisms of Treg cell development and function are discussed with particular emphasis on the forkhead transcription factor Foxp3.
Abstract: The random generation of antigen receptors in developing lymphocytes results in a considerable risk of autoimmunity. Regulatory T cells (T(reg) cells) act in a dominant, trans-acting way to actively suppress immune activation and maintain immune tolerance. Here, we discuss the principal advances in our understanding of the molecular mechanisms of T(reg) cell development and function with particular emphasis on the forkhead transcription factor Foxp3. Accumulating evidence suggests that T(reg) cells represent a dedicated T cell lineage and that Foxp3 functions as the T(reg) cell lineage specification factor. The aggressive early-onset lymphoproliferative syndrome resulting from Foxp3 deficiency identifies T(reg) cells as vital mediators of immunological tolerance to self and Foxp3 as the mediator of the genetic mechanism of dominant tolerance.
TL;DR: The hypothesis that the variability of bacterial ligands such as LPS and their innate immune receptors is an important factor in determining the outcome of infectious disease is examined.
Abstract: Innate immune receptors recognize microorganism-specific motifs. One such receptor-ligand complex is formed between the mammalian Toll-like receptor 4 (TLR4)-MD2-CD14 complex and bacterial lipopolysaccharide (LPS). Recent research indicates that there is significant phylogenetic and individual diversity in TLR4-mediated responses. In addition, the diversity of LPS structures and the differential recognition of these structures by TLR4 have been associated with several bacterial diseases. This review will examine the hypothesis that the variability of bacterial ligands such as LPS and their innate immune receptors is an important factor in determining the outcome of infectious disease.
TL;DR: It is shown that most mouse and human NKT cells recognize glycosphingolipids from Sphingomonas, Gram-negative bacteria that do not contain lipopolysaccharide, and that these cells might be useful in providing protection from bacteria that cannot be detected by pattern recognition receptors such as Toll-like receptor 4.
Abstract: Natural killer T (NKT) cells constitute a highly conserved T lymphocyte subpopulation that has the potential to regulate many types of immune responses through the rapid secretion of cytokines. NKT cells recognize glycolipids presented by CD1d, a class I-like antigen-presenting molecule. They have an invariant T-cell antigen receptor (TCR) alpha-chain, but whether this invariant TCR recognizes microbial antigens is still controversial. Here we show that most mouse and human NKT cells recognize glycosphingolipids from Sphingomonas, Gram-negative bacteria that do not contain lipopolysaccharide. NKT cells are activated in vivo after exposure to these bacterial antigens or bacteria, and mice that lack NKT cells have a marked defect in the clearance of Sphingomonas from the liver. These data suggest that NKT cells are T lymphocytes that provide an innate-type immune response to certain microorganisms through recognition by their antigen receptor, and that they might be useful in providing protection from bacteria that cannot be detected by pattern recognition receptors such as Toll-like receptor 4.
TL;DR: In stable transplant patients, CD4+CD25+ and CD8+CD28- Treg have been recently shown to modulate immune response toward donor antigens in the indirect and direct pathway, respectively, raising the possibility that such Treg also have a role in the induction or maintenance of transplant tolerance in humans.
Abstract: It is now well recognized that regulatory T cells (Treg) play a central role in the control of both reactivity to self-antigens and alloimmune response. Several subsets of Treg with distinct phenotypes and mechanisms of action have now been identified. They constitute a network of heterogeneous CD4+ or CD8+T cell subsets and other minor T cell populations such as nonpolymorphic CD1d-responsive natural killer T cells. Treg not only play a main role in maintaining self-tolerance and preventing autoimmune disease but can also be induced by tolerance protocols and seemed to play a key role in preventing allograft rejection, as demonstrated in many animal models. Of particular interest, in stable transplant patients, CD4+CD25+ and CD8+CD28- Treg have been recently shown to modulate immune response toward donor antigens in the indirect and direct pathway, respectively. This finding raises the possibility that such Treg also have a role in the induction or maintenance of transplant tolerance in humans.
TL;DR: Lysosomal processing after autophagy may contribute to MHC class II–restricted surveillance of long-lived endogenous antigens including nuclear proteins relevant to disease.
Abstract: CD4+ T cells classically recognize antigens that are endocytosed and processed in lysosomes for presentation on major histocompatibility complex (MHC) class II molecules. Here, endogenous Epstein-Barr virus nuclear antigen 1 (EBNA1) was found to gain access to this pathway by autophagy. On inhibition of lysosomal acidification, EBNA1, the dominant CD4+ T cell antigen of latent Epstein-Barr virus infection, slowly accumulated in cytosolic autophagosomes. In addition, inhibition of autophagy decreased recognition by EBNA1-specific CD4+ T cell clones. Thus, lysosomal processing after autophagy may contribute to MHC class II-restricted surveillance of long-lived endogenous antigens including nuclear proteins relevant to disease.
TL;DR: The functions of these cells in both innate and adaptive immunity are discussed, and differing viewpoints regarding the generation and function of marginal zone B cells in rodents and primates are reconciled.
Abstract: ▪ Abstract Our views regarding the origins and functions of splenic marginal zone B cells have changed considerably over the past few years. Perspectives regarding the development and function of these cells vary considerably between investigators studying human and rodent immunology. Marginal zone B cells are now recognized to constitute a distinct naive B lymphoid lineage. Considerable progress has been made regarding the mechanisms involved in marginal zone B cell development in the mouse. Many of the molecular events that participate in the retention of this lineage of B cells in the marginal zone have been identified. Here, we discuss the functions of these cells in both innate and adaptive immunity. We also attempt to reconcile differing viewpoints regarding the generation and function of marginal zone B cells in rodents and primates.
TL;DR: Estimation of antitumor immune responses in mice after treatment of OVA-expressing B16-F0 tumors with single or fractionated doses of localized ionizing radiation suggests that localized radiation can increase both the generation of antitUMor immune effector cells and their trafficking to the tumor site.
Abstract: Immunotherapy of cancer is attractive because of its potential for specificity and limited side effects. The efficacy of this approach may be improved by providing adjuvant signals and an inflammatory environment for immune cell activation. We evaluated antitumor immune responses in mice after treatment of OVA-expressing B16-F0 tumors with single (15 Gy) or fractionated (5 x 3 Gy) doses of localized ionizing radiation. Irradiated mice had cells with greater capability to present tumor Ags and specific T cells that secreted IFN-gamma upon peptide stimulation within tumor-draining lymph nodes than nonirradiated mice. Immune activation in tumor-draining lymph nodes correlated with an increase in the number of CD45(+) cells infiltrating single dose irradiated tumors compared with nonirradiated mice. Similarly, irradiated mice had increased numbers of tumor-infiltrating lymphocytes that secreted IFN-gamma and lysed tumor cell targets. Peptide-specific IFN-gamma responses were directed against both the class I and class II MHC-restricted OVA peptides OVA(257-264) and OVA(323-339), respectively, as well as the endogenous class I MHC-restricted B16 tumor peptide tyrosinase-related protein 2(180-188). Adoptive transfer studies indicated that the increased numbers of tumor Ag-specific immune cells within irradiated tumors were most likely due to enhanced trafficking of these cells to the tumor site. Together these results suggest that localized radiation can increase both the generation of antitumor immune effector cells and their trafficking to the tumor site.
TL;DR: It is shown that APCs of the lymphoreticular system and of the CNS parenchyma are dispensable for the immune invasion of the central nervous system (CNS) and that a discrete population of vessel-associated dendritic cells (DCs) is present in human brain tissue.
Abstract: Immunization with myelin antigens leads to the development of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. The disease can also be induced by the transfer of encephalitogenic CD4+ T helper (T(H)) lymphocytes into naive mice. These T cells need to re-encounter their cognate antigen in the context of major histocompatibility complex (MHC) class II-bearing antigen-presenting cells (APCs) in order to recognize their target. The cell type and location of the APC mediating T-cell entry into the central nervous system (CNS) remain unknown. Here, we show that APCs of the lymphoreticular system and of the CNS parenchyma are dispensable for the immune invasion of the CNS. We also describe that a discrete population of vessel-associated dendritic cells (DCs) is present in human brain tissue. In mice, CD11c+ DCs alone are sufficient to present antigen in vivo to primed myelin-reactive T cells in order to mediate CNS inflammation and clinical disease development.
TL;DR: The response to RNA-associated autoantigens was markedly enhanced by IFN-α, a cytokine strongly linked to disease progression in patients with systemic lupus erythematosus (SLE), and this data implicate TLR recognition of endogenous ligands in the response to both DNA- and RNA- associated autoantIGens.
Abstract: Previous studies (Leadbetter, E.A., I.R. Rifkin, A.H. Hohlbaum, B. Beaudette, M.J. Shlomchik, and A. Marshak-Rothstein. 2002. Nature. 416:603-607; Viglianti, G.A., C.M. Lau, T.M. Hanley, B.A. Miko, M.J. Shlomchik, and A. Marshak-Rothstein. 2003. Immunity. 19:837-847) established the unique capacity of DNA and DNA-associated autoantigens to activate autoreactive B cells via sequential engagement of the B cell antigen receptor (BCR) and Toll-like receptor (TLR) 9. We demonstrate that this two-receptor paradigm can be extended to the BCR/TLR7 activation of autoreactive B cells by RNA and RNA-associated autoantigens. These data implicate TLR recognition of endogenous ligands in the response to both DNA- and RNA-associated autoantigens. Importantly, the response to RNA-associated autoantigens was markedly enhanced by IFN-alpha, a cytokine strongly linked to disease progression in patients with systemic lupus erythematosus (SLE). As further evidence that TLRs play a key role in autoantibody responses in SLE, we found that autoimmune-prone mice, lacking the TLR adaptor protein MyD88, had markedly reduced chromatin, Sm, and rheumatoid factor autoantibody titers.
TL;DR: The expression of the nuclear antigen Ki-67 correlates with other measurements of proliferation, including S-phase and bromodeoxyuridine uptake, which is a sign of poor prognosis associated with a good chance of clinical response to chemotherapy.
Abstract: Molecular markers have been extensively investigated with a view to providing early and accurate information on long-term outcome and prediction of response to treatment of early breast cancer Proliferation is a key feature of the progression of tumors and is now widely estimated by the immunohistochemical assessment of the nuclear antigen Ki-67 The expression of Ki-67 correlates with other measurements of proliferation, including S-phase and bromodeoxyuridine uptake High Ki-67 is a sign of poor prognosis associated with a good chance of clinical response to chemotherapy, but its independent significance is modest and does not merit measurements in most routine clinical scenarios However, its application as a pharmacodynamic intermediate marker of the effectiveness of medical therapy holds great promise for rapid evaluation of new drugs
TL;DR: Monitoring the homing, expansion, and effector function of both subsets in draining and nondraining lymph nodes shows that CD8 cells expand to the same extent and produce similar levels of IFN-γ in the presence or absence of Ag-specific Treg, which abrogate CD8 T cell-mediated tumor rejection by specifically suppressing the cytotoxicity of expandedCD8 cells.
Abstract: Cancer patients can harbor significant numbers of CD8 and CD4 T cells with specificities to tumor antigens (Ags). Yet, in most cases, such T cells fail to eradicate the tumor in vivo. Here, we investigated the interference of Ag-specific CD4+CD25+ regulatory T cells (Treg) with the tumor-specific CD8 T cell immune response in vivo, by monitoring the homing, expansion, and effector function of both subsets in draining and nondraining lymph nodes. The results show that CD8 cells expand to the same extent and produce similar levels of IFN-γ in the presence or absence of Ag-specific Treg. Nevertheless, these Treg abrogate CD8 T cell-mediated tumor rejection by specifically suppressing the cytotoxicity of expanded CD8 cells. The molecular mechanism of suppression involves TGF-β because expression of a dominant-negative TGF-β receptor by tumor-specific CD8 cells renders them resistant to suppression and is associated with tumor rejection and unimpaired cytotoxicity.
TL;DR: It is found that, in addition to CD4+ T-cell help, generation of T-dependent antigen-specific antibody responses requires activation of TLRs in B cells.
Abstract: Toll-like receptors (TLRs) detect microbial infection and have an essential role in the induction of immune responses. TLRs can directly induce innate host defence responses, but the mechanisms of TLR-mediated control of adaptive immunity are not fully understood. Although TLR-induced dendritic cell maturation is required for activation of T-helper (T(H)) cells, the role of TLRs in B-cell activation and antibody production in vivo is not yet known. Here we show that activation and differentiation of T(H) cells is not sufficient for the induction of T-dependent B-cell responses. We find that, in addition to CD4+ T-cell help, generation of T-dependent antigen-specific antibody responses requires activation of TLRs in B cells.
TL;DR: This work reviews the cellular and molecular regulators of this dynamic process with emphasis on the multiple memory B cell fates that develop in vivo.
Abstract: ▪ Abstract Helper T (Th) cell–regulated B cell immunity progresses in an ordered cascade of cellular development that culminates in the production of antigen-specific memory B cells. The recognition of peptide MHC class II complexes on activated antigen-presenting cells is critical for effective Th cell selection, clonal expansion, and effector Th cell function development (Phase I). Cognate effector Th cell–B cell interactions then promote the development of either short-lived plasma cells (PCs) or germinal centers (GCs) (Phase II). These GCs expand, diversify, and select high-affinity variants of antigen-specific B cells for entry into the long-lived memory B cell compartment (Phase III). Upon antigen rechallenge, memory B cells rapidly expand and differentiate into PCs under the cognate control of memory Th cells (Phase IV). We review the cellular and molecular regulators of this dynamic process with emphasis on the multiple memory B cell fates that develop in vivo.
TL;DR: It is concluded that the autoimmune-predisposing allele of the gene PTPN22 is a gain-of-function mutant.
Abstract: A SNP in the gene PTPN22 is associated with type 1 diabetes, rheumatoid arthritis, lupus, Graves thyroiditis, Addison disease and other autoimmune disorders. T cells from carriers of the predisposing allele produce less interleukin-2 upon TCR stimulation, and the encoded phosphatase has higher catalytic activity and is a more potent negative regulator of T lymphocyte activation. We conclude that the autoimmune-predisposing allele is a gain-of-function mutant.
TL;DR: DCs in vivo degraded internalized antigens slowly and thus retained antigen in lymphoid organs for extended periods, and limited lysosomal proteolysis also favored antigen presentation.
Abstract: Antigen-presenting cells (APCs) internalize antigens and present antigen-derived peptides to T cells. Although APCs have been thought to exhibit a well-developed capacity for lysosomal proteolysis, here we found that they can exhibit two distinct strategies upon antigen encounter. Whereas macrophages contained high levels of lysosomal proteases and rapidly degraded internalized proteins, dendritic cells (DCs) and B lymphocytes were protease-poor, resulting in a limited capacity for lysosomal degradation. Consistent with these findings, DCs in vivo degraded internalized antigens slowly and thus retained antigen in lymphoid organs for extended periods. Limited lysosomal proteolysis also favored antigen presentation. These results help explain why DCs are able to efficiently accumulate, process, and disseminate antigens and microbes systemically for purposes of tolerance and immunity.
TL;DR: The present status of the molecular structures and functions of various defense components that participated in innate immune systems have been established in Arthropoda, such as, insects, the horseshoe crab, freshwater crayfish, and the protochordata ascidian are described.
Abstract: Invertebrate animals, which lack adaptive immune systems, have developed other systems of biological host defense, so called innate immunity, that respond to common antigens on the cell surfaces of potential pathogens During the past two decades, the molecular structures and functions of various defense components that participated in innate immune systems have been established in Arthropoda, such as, insects, the horseshoe crab, freshwater crayfish, and the protochordata ascidian These defense molecules include phenoloxidases, clotting factors, complement factors, lectins, protease inhibitors, antimicrobial peptides, Toll receptors, and other humoral factors found mainly in hemolymph plasma and hemocytes These components, which together compose the innate immune system, defend invertebrate from invading bacterial, fungal, and viral pathogens This review describes the present status of our knowledge concerning such defensive molecules in invertebrates
TL;DR: Results demonstrate a unique function for LP-derived CD103+ MLN DCs in the generation of gut-tropic effector T cells in vitro.
Abstract: Gut-associated lymphoid tissue (GALT) dendritic cells (DCs) display a unique ability to generate CCR9 + α 4 β 7 + gut-tropic CD8 + effector T cells. We demonstrate efficient induction of CCR9 and α 4 β 7 on CD8 + T cells in mesenteric lymph nodes (MLNs) after oral but not intraperitoneal (i.p.) antigen administration indicating differential targeting of DCs via the oral route. In vitro, lamina propria (LP)–derived DCs were more potent than MLN or Peyer's patch DCs in their ability to generate CCR9 + α 4 β 7 + CD8 + T cells. The integrin α chain CD103 ( α E) was expressed on almost all LP DCs, a subset of MLN DCs, but on few splenic DCs. CD103 + MLN DCs were reduced in number in CCR7 − / − mice and, although CD8 + T cells proliferated in the MLNs of CCR7 − / − mice after i.p. but not oral antigen administration, they failed to express CCR9 and had reduced levels of α 4 β 7. Strikingly, although CD103 + and CD103 − MLN DCs were equally potent at inducing CD8 + T cell proliferation and IFN- γ production, only CD103 + DCs were capable of generating gut-tropic CD8 + effector T cells in vitro. Collectively, these results demonstrate a unique function for LP-derived CD103 + MLN DCs in the generation of gut-tropic effector T cells.
TL;DR: PCR should not be used as the sole laboratory modality to support a clinical diagnosis of extracutaneous LB, and PCR positivity in seronegative patients suspected of having late manifestations of LB most likely represents a false-positive result.
Abstract: A large amount of knowledge has been acquired since the original descriptions of Lyme borreliosis (LB) and of its causative agent, Borrelia burgdorferi sensu stricto. The complexity of the organism and the variations in the clinical manifestations of LB caused by the different B. burgdorferi sensu lato species were not then anticipated. Considerable improvement has been achieved in detection of B. burgdorferi sensu lato by culture, particularly of blood specimens during early stages of disease. Culturing plasma and increasing the volume of material cultured have accomplished this. Further improvements might be obtained if molecular methods are used for detection of growth in culture and if culture methods are automated. Unfortunately, culture is insensitive in extracutaneous manifestations of LB. PCR and culture have high sensitivity on skin samples of patients with EM whose diagnosis is based mostly on clinical recognition of the lesion. PCR on material obtained from extracutaneous sites is in general of low sensitivity, with the exception of synovial fluid. PCR on synovial fluid has shown a sensitivity of up to >90% (when using four different primer sets) in patients with untreated or partially treated Lyme arthritis, making it a helpful confirmatory test in these patients. Currently, the best use of PCR is for confirmation of the clinical diagnosis of suspected Lyme arthritis in patients who are IgG immunoblot positive. PCR should not be used as the sole laboratory modality to support a clinical diagnosis of extracutaneous LB. PCR positivity in seronegative patients suspected of having late manifestations of LB most likely represents a false-positive result. Because of difficulties in direct methods of detection, laboratory tests currently in use are mainly those detecting antibodies to B. burgdorferi sensu lato. Tests used to detect antibodies to B. burgdorferi sensu lato have evolved from the initial formats as more knowledge on the immunodominant antigens has been collected. The recommendation for two-tier testing was an attempt to standardize testing and improve specificity in the United States. First-tier assays using whole-cell sonicates of B. burgdorferi sensu lato need to be standardized in terms of antigen composition and detection threshold of specific immunoglobulin classes. The search for improved serologic tests has stimulated the development of recombinant protein antigens and the synthesis of specific peptides from immunodominant antigens. The use of these materials alone or in combination as the source of antigen in a single-tier immunoassay may someday replace the currently recommended two-tier testing strategy. Evaluation of these assays is currently being done, and there is evidence that certain of these antigens may be broadly cross-reactive with the B. burgdorferi sensu lato species causing LB in Europe.
TL;DR: Analysis of activation of naive proteolipid protein (PLP)139–151-specific T cells in SJL mice undergoing PLP178–191-induced R-EAE or TMEV-IDD suggests that naive T cells enter the inflamed CNS and are activated by local APCs, possibly DCs, to initiate epitope spreading.
Abstract: Chronic progression of two T cell–mediated central nervous system (CNS) demyelinating models of multiple sclerosis, relapsing EAE (R-EAE) and Theiler's murine encephalomyelitis virus–induced demyelinating disease (TMEV-IDD) is dependent on the activation of T cells to endogenous myelin epitopes (epitope spreading). Using transfer of carboxyfluorescein succinyl ester (CFSE)-labeled T-cell receptor (TCR)-transgenic T cells and mixed bone marrow chimeras, we show that activation of naive proteolipid protein (PLP)139–151-specific T cells in SJL mice undergoing PLP178–191-induced R-EAE or TMEV-IDD occurs directly in the CNS and not in the cervical lymph nodes or other peripheral lymphoid organs. Examination of the antigen-presentation capacity of antigen-presenting cell (APC) populations purified from the CNS of mice with PLP178–191-induced R-EAE shows that only F4/80−CD11c+CD45hi dendritic cells (DCs) efficiently present endogenous antigen to activate naive PLP139–151-specific T cells in vitro. In contrast, DCs as well as F4/80+CD45hi macrophages and F4/80+CD45lo microglia activate a PLP139–151-specific helper T cell line. The data suggest that naive T cells enter the inflamed CNS and are activated by local APCs, possibly DCs, to initiate epitope spreading.
TL;DR: A "safety switch" that can be stably and efficiently expressed in human T cells without impairing phenotype, function, or antigen specificity is described, based on a modified human caspase 9 fused to a human FK506 binding protein to allow conditional dimerization using a small molecule pharmaceutical.