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Lymphoid Organs (lymphoid + organ)
Kinds of Lymphoid Organs Selected AbstractsExpression of the PACAP-immunoreactivity in the Lymphoid Organs of the DuckANATOMIA, HISTOLOGIA, EMBRYOLOGIA, Issue 2005C. Squillacioti Introduction:, The interactions occurring between nervous and immune systems are well documented. These interactions involve several types of chemical messengers including hormones, cytokines, classic neurotransmitters and neuropeptides. It has been observed that the lymphoid organs receive a dense peptidergic innervation and immune cells produce neuropeptides. Neuropeptides, in turn, are involved in the regulation of the inflammatory processes and in the maturation of the lymphoid organs. Several studies have demonstrated that the immunomodulatory neuropeptides and their receptors are expressed in the thymus and bursa of fabricius. PACAP is a glucagon/VIP/secretin family peptide. It was originally isolated from the ovine hypothalamus and then it was found in the autonomic nervous system. PACAP is involved in the regulation of the hypothalamic-pituitary function, neurotransmission and neuromodulation. In the immune system, PACAP is expressed in lymphoid tissues of the rat and in the lymphocytes of the duck GALT. PACAP, therefore, could be a messenger of the dialogue between nervous and immune system. It may have a role in the regulation of the inflammatory processes by stimulating histamine and serotonin and modulating the production of the cytokines in immune cells. Methods:, Immunohistochemistry on paraffin-embedded sections of thymus and bursa of fabricius of the duck of different ages by using an antibody anti-PACAP38. Results and Discussion:, In the thymus, PACAP-immunoreactivity was found in lymphoid cells and, with a lesser extent, in epithelial reticular cells. The immunoreactive lymphocytes were primarily observed in the interlobular septa in close vicinity to the interlobular veins. The number of positive lymphocytes increased with ageing. In the bursa of fabricius, PACAP-IR was found in nerve fibres and in a few lymphoid cells. These results suggest that PACAP could play a role in the maturation and involution of these organs and in the immune functions. [source] Neurotrophin Receptor-like Proteins in the Bovine (Bos taurus) Lymphoid Organs, with Special Reference to Thymus and SpleenANATOMIA, HISTOLOGIA, EMBRYOLOGIA, Issue 4 2001M. B. Levanti Increasing evidence suggests that neurotrophins could regulate immune functions acting directly or indirectly on immunocompetent cells. The indirect pathway involves stromal cells of the primary and secondary lymphoid organs. In the present study the occurrence of Trk proteins (TrkA, TrkB and TrkC), regarded as the high-affinity signal-transducing receptors for neurotrophins, was investigated in cow lymphoid organs using immunohistochemistry. The thymus and spleen of both fetal and adult animals, and the palatine tonsils, lymph nodes and Peyer's patches of adult animals, were analysed. Unidentified cells displaying TrkA-like immunoreactivity were found in the fetal thymus, whereas those expressing this protein in the adult gland were identified as epithelial cells. In the spleen, immunoreactive TrkA was observed in cells of the white pulp. TrkB immunoreactivity in both fetal and adult thymus and spleen was localized in monocyte/macrophage cells. As a rule, TrkC was absent from the thymus and the spleen independent of the animal's age. Different types of stromal cells, but never the lymphocytes themselves, displayed TrkA, TrkB, or TrkC immunoreactivity in the other lymphoid organs analysed. As in other vertebrate species, Trk proteins in the lymphoid organs of the cow were localized in the stromal, non-lymphoid cells, thus suggesting that neurotrophins might regulate the immune function acting indirectly on lymphocytes. [source] Genetic dissection of thymus development in mouse and zebrafishIMMUNOLOGICAL REVIEWS, Issue 1 2003Thomas Boehm Summary:, Lymphoid organs represent a specialized microenvironment for interaction of stromal and lymphoid cells. In primary lymphoid organs, these interactions are required to establish a self-tolerant repertoire of lymphocytes. While detailed information is available about the genes that control lymphocyte differentiation, little is known about the genes that direct the establishment and differentiation of principal components of such microenvironments. Here, we discuss genetic studies addressing the role of thymic epithelial cells (TECs) during thymopoiesis. We have identifed an evolutionarily conserved key regulator of TEC differentiation, Foxn1, that is required for the immigration of prothymocytes into the thymic primordium. Because Foxn1 specifies the prospective endodermal domain that gives rise to thymic epithelial cells, it can be used to identify the evolutionary origins of this specialized cell type. In the course of these studies, we have found that early steps of thymus development in zebrafish are very similar to those in mice. Subsequently, we have used chemical mutagenesis to derive zebrafish lines with aberrant thymus development. Strengths and weaknesses of mouse and zebrafish models are largely complementary such that genetic analysis of mouse and zebrafish mutants may lead to a better understanding of thymus development. [source] The pericyte and stromal cell marker CD248 (endosialin) is required for efficient lymph node expansionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2010Siân Lax Abstract CD248 is a cell surface receptor that specifically identifies fibroblasts and pericytes during development and in association with cancer and inflammation. However, its function is poorly defined and its role in lymphoid organs not studied. Here, we used (4-hydroxy-3-nitrophenyl)acetyl chicken ,-globulin immunisation and mice lacking CD248 to study whether CD248 modulates popliteal LN (pLN) expansion and subsequent immune responses. We have found that CD248 is required for complete pLN expansion but not for co-ordination of B and T cell compartmentalisation or antibody production following (4-hydroxy-3-nitrophenyl)acetyl chicken ,-globulin immunisation. In vitro, we show that CD248 expression in human MG63 stromal cells and mouse embryonic fibroblasts leads to a pro-proliferative and pro-migratory phenotype. This correlates with a proliferating CD248+ population observed in vivo during pLN expansion. Taken together, these data highlight a role for CD248 in secondary lymphoid organ remodelling during adaptive immune responses. [source] Three tetraspanins from Chinese shrimp, Fenneropenaeus chinensis, may play important roles in WSSV infectionJOURNAL OF FISH DISEASES, Issue 1 2010B Wang Abstract Three members of the tetraspanin/TM4SF superfamily were cloned from Chinese shrimp, Fenneropenaeus chinensis. The deduced amino acid sequences of the three proteins have typical motifs of the tetraspanin/TM4SF superfamily. Phylogenetic analysis of the proteins, together with the known tetraspanins of invertebrates and vertebrates, revealed that they belong to different tetraspanin subfamilies: CD9, CD63 and tetraspanin-3. The three cloned genes of CD9, CD63 and tetraspanin-3 showed apparently different tissue distributions. The CD9 gene (FcCD9) was specifically expressed in the hepatopancreas. While for the CD63 gene (FcCD63), the highest expression was detected in nerves, epidermis and heart, with low expression in haemocytes, ovary, gill, hepatopancreas and stomach and no expression in intestine, muscle and lymphoid organ. Compared with FcCD9 and FcCD63, the tetraspanin-3 gene (FcTetraspanin-3) was more broadly expressed and its highest expression was detected in the intestine. Its expression in nerves was lower than in the intestine, but was higher than in other tissues. Expression in haemocytes, ovary and muscle was much lower than in other tissues. The expression profiles of FcCD9, FcCD63 and FcTetraspanin-3 in different tissues, including haemocytes, lymphoid organ and hepatopancreas, were compared by real-time PCR when shrimp were challenged by live white spot syndrome virus (WSSV) and heat-inactivated WSSV. All three tetraspanins were markedly up-regulated in the live WSSV-challenged shrimp tissues. The data suggested that the three cloned members of TM4SF superfamily in Chinese shrimp may play a key role in the route of WSSV infection. [source] Apoptosis does not play an important role in the resistance of ,immune'Penaeus japonicus against white spot syndrome virusJOURNAL OF FISH DISEASES, Issue 1 2004J L Wu Abstract We previously demonstrated that kuruma shrimp, Penaeus japonicus, exposed to white spot syndrome virus (WSSV) became resistant (,immune' shrimp) to subsequent challenge with the virus. The present study investigated the role of apoptosis in the ,immune' shrimp during a secondary challenge with WSSV. When naive kuruma shrimp were intramuscularly injected with WSSV at a high or low dose, apoptosis was often detected by TUNEL assay in the lymphoid organ (LO), mainly in the early stage of the infection. A significantly higher incidence of apoptosis was observed in the LO of the shrimp injected with the high dose of WSSV (cumulative mortality: 100%) than in the shrimp injected with the low dose (cumulative mortality: 0%). When ,immune' and naive shrimp were injected with an equal dose of WSSV, the incidence of apoptosis was significantly lower in the ,immune' shrimp than in the naive shrimp. This difference is assumed to result from a substantial reduction of the virus by humoral neutralizing factor in the ,immune' shrimp. These results suggest that apoptosis is not a principal protective factor in ,immune' shrimp. [source] Sentinel lymph node as a target of molecular diagnosis of lymphatic micrometastasis and local immunoresponse to malignant cellsCANCER SCIENCE, Issue 3 2008Hiroya Takeuchi The sentinel lymph node (SLN) is defined as the lymph node(s) first receiving lymphatic drainage from the site of the primary tumor. The histopathological status of SLN is one of the most significant predictors of recurrence and overall survival for most clinical stage I/II solid tumors. Recent progress in molecular techniques has demonstrated the presence of micrometastatic tumor cells in SLN. There is now a growing body of data to support the clinical relevance of SLN micrometastasis in a variety of solid tumors. Increasing the sensitivity of occult tumor cell detection in the SLN, using molecular-based analysis, should enable a more accurate understanding of the clinical significance of various patterns of micrometastatic nodal disease. The establishment of metastasis to SLN might not be simply reflected by the flow dynamics of lymphatic fluid that drains from the primary site to the SLN, and the transportation of viable cancer cells. Recent studies have demonstrated that primary tumors can actively induce lymphangiogenesis and promote SLN metastasis. Moreover chemokine receptors in tumor cells may facilitate organ-specific tumor metastasis in many human cancers and some experimental models. In contrast, recent clinical and preclinical studies regard SLN as the first lymphoid organ to respond to tumor antigenic stimulation. SLN dramatically show morphological, phenotypical and functional changes that indicate immune suppression by tumor cells. The immune suppression in SLN results in failure of prevention or eradication of tumor metastasis. The mechanism of immunomodulation remains unclear; however, several regulatory molecules produced by tumor cells and tumor-associated macrophages or lymphocytes are likely to be responsible for inducing the immune suppression in SLN. Further studies may develop a novel immunotherapy that overcomes tumor-induced immune suppression and can prevent or eradicate SLN metastasis. (Cancer Sci 2008; 99: 441,450) [source] The pericyte and stromal cell marker CD248 (endosialin) is required for efficient lymph node expansionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2010Siân Lax Abstract CD248 is a cell surface receptor that specifically identifies fibroblasts and pericytes during development and in association with cancer and inflammation. However, its function is poorly defined and its role in lymphoid organs not studied. Here, we used (4-hydroxy-3-nitrophenyl)acetyl chicken ,-globulin immunisation and mice lacking CD248 to study whether CD248 modulates popliteal LN (pLN) expansion and subsequent immune responses. We have found that CD248 is required for complete pLN expansion but not for co-ordination of B and T cell compartmentalisation or antibody production following (4-hydroxy-3-nitrophenyl)acetyl chicken ,-globulin immunisation. In vitro, we show that CD248 expression in human MG63 stromal cells and mouse embryonic fibroblasts leads to a pro-proliferative and pro-migratory phenotype. This correlates with a proliferating CD248+ population observed in vivo during pLN expansion. Taken together, these data highlight a role for CD248 in secondary lymphoid organ remodelling during adaptive immune responses. [source] Splenic stromal cells mediate IL-7 independent adult lymphoid tissue inducer cell survivalEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 2 2010Tie Zheng Hou Abstract Lymphoid tissue inducer cells (LTi) play an important role in the development of lymphoid tissue in embryos. Adult CD4+CD3, LTi-like cells present a similar phenotype and gene expression to their embryonic counterpart and have important roles in CD4+ T-cell memory and lymphoid tissue recovery following viral infection. However, adult LTi-like cells are heterogeneous populations and the factors that regulate their survival and accumulation within secondary lymphoid organs remain unclear, in particular whether the T-zone stroma is involved. Here we report the identification and characterization of a distinct subset of podoplanin+ murine splenic stromal cells that support adult LTi-like cell survival. We have identified and isolated CD45,podoplanin+ stromal cell populations which have a similar but distinct phenotype to T-zone reticular cells in LN. CD45,podoplanin+ fibroblast-like cells mediate LTi-like cell survival in vitro; surprisingly this was not dependent upon IL-7 as revealed through blocking Ab experiments and studies using LTi-like cells unable to respond to , chain cytokines. Our findings show that adult LTi-like cells require extrinsic signals from podoplanin+ splenic stromal cells to survive and suggest that IL-7 is not necessary to mediate their survival in the adult spleen. [source] Strategies for optimizing targeting and delivery of mucosal HIV vaccinesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2009Jeffrey D. Ahlers Abstract Effective frontline defenses against HIV-1 will require targeting vaccines to mucosal tissue in order to induce ,, CD8+ lymphocytes in mucosal effector sites (lamina propria and intraepithelial compartment) as well as antibody secreting plasma cells that can neutralize and limit free virus. A concerted second wave of assault against the virus will require the activation and recruitment of antigen specific memory CD4+ and CD8+ T cells in mesenteric lymph nodes and distal secondary lymphoid organs. New delivery strategies targeting the "right" DC subsets in combination with delivery of mucosal adjuvants and innate signals for activating DC will be essential for mucosal vaccines in order to circumvent the naturally tolerogenic environment and the induction of Tregs. Mucosal delivery of antigen in combination with inflammatory signals has been shown to empower systemic immunization by directing responses to mucosal sites for imprinting optimum mucosal memory. Here, we discuss novel vaccine strategies and adjuvants for optimizing mucosal delivery of HIV vaccines. [source] IL-23-driven encephalo-tropism and Th17 polarization during CNS-inflammation in vivoEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2009Gabor Gyülvészi Abstract IL-23 but not IL-12 is essential for the development of autoimmune tissue inflammation in mice. Conversely, IL-12 and IL-23 impact on the polarization of Th1 and Th17 cells, respectively. While both polarized T helper populations can mediate autoimmune inflammation, their redundancy in the pathogenesis of EAE indicates that IL-23 exerts its crucial influence on the disease independent of its T helper polarizing capacity. To study the impact of IL-23 and IL-12 on the behavior of encephalitogenic T cells in vivo, we generated BM-chimeric mice in which we can trace individual populations of IL-23 or IL-12 responsive T helper cells during EAE. We observed that T cells, which lack IL-12R,1 (no IL-12 and IL-23 signaling), fail to invade the CNS and do not acquire a Th17 phenotype. In contrast, loss of IL-12 signaling prevents Th1 polarization but does not prevent T-cell entry into the CNS. The loss of IL-12R engagement does not appear to alter T-cell expansion but leads to their accumulation in secondary lymphoid organs. We found that IL-23 licenses T cells to invade the target tissue and to exert their effector function, whereas IL-12 is critical for Th1 differentiation, but does not influence the pathogenic capacity of auto-reactive T helper cells in vivo. [source] Antigen-loaded ER microsomes from APC induce potent immune responses against viral infectionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 1 2009Vassiliki Sofra Abstract Although matured DC are capable of inducing effective primary and secondary immune responses in vivo, it is difficult to control the maturation and antigen loading in vitro. In this study, we show that ER-enriched microsomal membranes (microsomes) isolated from DC contain more peptide-receptive MHC I and II molecules than, and a similar level of costimulatory molecules to, their parental DC. After loading with defined antigenic peptides, the microsomes deliver antigenic peptide,MHC complexes (pMHC) to both CD4 and CD8 T cells effectively in vivo. The peptide-loaded microsomes accumulate in peripheral lymphoid organs and induce stronger immune responses than peptide-pulsed DC. The microsomal vaccines protect against acute viral infection. Our data demonstrate that peptide,MHC complexes armed microsomes from DC can be an important alternative to DC-based vaccines for protection from viral infection. [source] Vaccinia virus impairs directional migration and chemokine receptor switch of human dendritic cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2007Abstract A crucial event for the induction of an anti-viral immune response is the coordinated, phenotype-dependent migration of dendritic cells (DC) to sites of infection and secondary lymphoid organs. Here we show that the vaccinia virus (VV) strains Western Reserve (WR) and modified virus Ankara (MVA) inhibit directional migration of mature DC toward the lymphoid chemokines CCL19 and CXCL12 without affecting surface expression of the respective chemokine receptors or impairing undirected cellular locomotion. Instead, infection with VV results in a deficiency of extracellular signal-regulated kinase-1 and a disturbance of intracellular calcium mobilization, indicating a viral interference with signaling events downstream of the surface chemokine receptors. In immature DC, apart from inhibiting chemokine-induced migration of infected DC, infection with both VV strains increases expression of the inflammatory chemokine receptors CCR1 and CXCR1 on non-infected bystander DC, which depends on the activity of IFN-,. Although functional, these chemokine receptors are resistant to lipopolysaccharide-induced down-regulation. In addition, VV-infected and non-infected bystander DC fail to up-regulate the lymphoid chemokine receptor CCR7 upon activation, together pointing to a disability to undergo the chemokine receptor switch. This study shows that VV targets directional migration of professional antigen-presenting cells at multiple functional levels, revealing a potent viral strategy of immune escape. See accompanying commentary: http://dx.doi.org/10.1002/eji.200737215 [source] NK cells of human secondary lymphoid tissues enhance T cell polarization via IFN-, secretionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2006Barbara Morandi Abstract Human secondary lymphoid tissues harbor NK cells that predominantly secrete cytokines in response to activation. Here, we demonstrate that these immunoregulatory NK cells assist in the Th1 polarization of primary immune responses, induced by dendritic cells. Tonsilar, but not peripheral blood NK cells enhanced the expansion of IFN-,-producing CD4+ T cells via their superior ability to produce IFN-,. Addition of IFN-, increased Th1 polarization while antibody blocking of this cytokine abolished NK cell-dependent Th1 polarization. Our data suggest that NK cells in secondary lymphoid organs assist priming of Th1 cells via cytokine secretion and this effect should be harnessed during vaccination against viruses and tumors. [source] Transient T,cell accumulation in lymph nodes and sustained lymphopenia in mice treated with FTY720EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2005Margaret Abstract FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride) is an orally available immunomodulatory agent that induces severe peripheral blood lymphopenia. Most studies of these lymphopenic effects have been limited to short-term exposure to FTY720. FTY720 alters the ability of lymphocytes to respond to sphingosine-1-phosphate (S1P) through S1P receptors, particularly S1P1. FTY720 affects different leukocyte populations and their trafficking through major lymphoid organs. We show the dynamics of CD4,T, CD8,T, and B,lymphocyte recirculation in all major lymphoid compartments during 21-day FTY720 treatment of normal C57BL/6 mice. Following a transient increase in peripheral lymph nodes and Peyer's patches, lymphocyte recirculation reaches a new steady state. Other lymphoid organs show transient changes in lymphocyte composition with various patterns. At 21,days of FTY720 treatment, total body lymphocyte content is reduced by 20% and blood lymphocytes by 80%. Modeling suggests that the new steady state is due to a combination of reduced naive lymphocyte release from the thymus and a transient reduction of lymphocyte egress from lymph nodes. Our data indicate that the commonly held belief that FTY720 blocks lymphocyte egress from lymph nodes cannot fully explain the lymphocyte dynamics observed with prolonged treatment. [source] Depletion of immature B,cells during Trypanosoma cruzi infection: involvement of myeloid cells and the cyclooxygenase pathwayEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2005Elina Zuniga Abstract The ability of a microorganism to elicit or evade B,cell responses represents a determinant factor for the final outcome of an infection. Although pathogens may subvert humoral responses at different stages of B,cell development, most studies addressing the impact of an infection on the B,cell compartment have focused on mature B,cells within peripheral lymphoid organs. Herein, we report that a protozoan infection, i.e. a Trypanosoma cruzi infection, induces a marked loss of immature B,cells in the BM, which also compromises recently emigrated B,cells in the periphery. The depletion of BM immature B,cells is associated with an increased rate of apoptosis mediated by a parasite-indirect mechanism in a Fas/FasL-independent fashion. Finally, we demonstrated that myeloid cells play an important role in B,cell depletion, since CD11b+ BM cells from infected mice secrete a product of the cyclooxygenase pathway that eliminates immature B,cells. These results highlight a previously unrecognized maneuver used by a protozoan parasite to disable B,cell generation, limiting host defense and favoring its chronic establishment. [source] Polymerase,, is up-regulated during the T,cell-dependent immune response and its deficiency alters developmental dynamics of spleen centroblastsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2005Daniel Lucas Abstract Mammalian DNA polymerase,, (Pol,), preferentially expressed in secondary lymphoid organs, is shown here to be up-regulated in germinal centers after immunization. Alternative splicing appears to be part of Pol, regulation during an immune response. We generated Pol,-deficient mice that are viable and show no anatomical malformation or serious alteration in lymphoid populations, with the exception of an underrepresentation of the B,cell compartment. Young and aged homozygous Pol,,/, mice generated similar immune responses after immunization with the hapten (4-hydroxy-3-nitrophenyl)acetyl (NP) coupled to chicken gammaglobulin (CGG), compared with their wild-type littermates. Nonetheless, the kinetics of development of the centroblast population showed significant differences. Hypermutation analysis of the rearranged heavy chain intron region in centroblasts isolated from NP-CGG-immunized Pol,,/, mice showed a similar quantitative and qualitative somatic mutation spectrum, but a lower representation of heavily mutated clones. These results suggest that although it is not a critical partner, Pol, modulates the in vivo somatic hypermutation process. [source] Specificity, magnitude, and kinetics of MOG-specific CD8+ T,cell responses during experimental autoimmune encephalomyelitisEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 1 2005Mandy Abstract Experimental autoimmune encephalomyelitis (EAE) has traditionally been thought to be almost exclusively mediated by CD4+ effector T,cells. Here, we provide evidence for the existence of mouse CD8+ T,cells that are specific for an epitope of the myelin oligodendrocyte glycoprotein (MOG). Using a panel of truncated MOG peptides, we have identified the minimal epitope recognized by these T,cells as MOG,37,46. This peptide, while possessing relatively low affinity for H-2Db, efficiently stimulates IFN-, production from MOG-specific CD8+ T,cell lines in vitro and induces EAE in vivo. To further characterize the magnitude and kinetics of expansion of the MOG-specific CD8+ T,cell population in vivo, we used MOG,37,50/H-2Db MHC tetramers to visualize MOG-specific CD8+ effectors in the peripheral lymphoid organs and central nervous system during the course of EAE induction and progression. Our results identify MOG-specific CD8+ T,cells in the central nervous system prior to and after the onset of disease, suggesting that CD8+ T,cells are a possible target for therapeutic intervention during EAE. [source] Prevention of diabetes in NOD mice at a late stage by targeting OX40/OX40 ligand interactionsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2004Syamasundar Abstract Autoreactive T,cells play a major role in the development of insulin-dependent diabetes mellitus, suggesting that costimulatory molecules that regulate T,cell responses might be essential for disease progression. In NOD mice, CD28/B7 and CD40/CD40 ligand,(L) interactions control the onset of diabetes from 2 to 4,weeks of age, but blocking these molecules has little effect after this time. Hence, it is possible that other ligand/receptor pairs control a later phase of disease. We now show that OX40 is expressed on CD4 and CD8 T,cells several weeks prior to islet destruction, which is initiated around weeks,12,14, and that OX40L is present on dendritic cells in both secondary lymphoid organs and the pancreas from 11 to 13,weeks of age. Blocking OX40L at 6, 9, or 15,weeks after birth had little effect on disease; however, inhibiting OX40/OX40L interactions at week,12, or continuous treatment from week,12 onwards, significantly reduced the incidence of diabetes. Histological examination showed that islet destruction was prevented and insulitis reduced by targeting OX40L. These studies show that OX40/OX40L interactions form a late checkpoint in diabetes development and suggest that these molecules are realistic targets for therapeutic intervention. [source] Myeloid marker expression on antiviral CD8+ T,cells following an acute virus infectionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2003Yinling Lin Abstract CD11b, CD11c, and F4/80 are normally used to define dendritic cell and/or macrophage populations. In this study, the expression of all three markers was observed on CD8+ T,cells following infection of mice with several distinct viruses. Using lymphocytic choriomeningitis virus as a model virus, it was found that relatively more CD11b+CD8+ and CD11c+CD8+ T,cells were present in the periphery than in primary lymphoid organs; in contrast, the F4/80+CD8+ T,cell population was more prevalent in the spleen. All three myeloid markers were detected on virus-specific CTL. The expression of CD11b and CD11c on CD8+ T,cells correlated with their level of CTL activity, whereas the F4/80+CD8+ T,cell population increased after the peak of the CTL response but did not have higher CTL activity. These data suggest that there is a differential induction of CD11b, CD11c, and F4/80 on virus-specific CD8+ T,cells following an acute virus infection. [source] Trypanosoma cruzi infection modulates intrathymic contents of extracellular matrix ligands and receptors and alters thymocyte migrationEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2003Vinícius Cotta-de-Almeida Abstract Several T cell abnormalities have been described in the course of acute Trypanosoma cruzi infection in mice, including severe effects on the thymus. In the present study, looking at the expression of extracellular matrix ligands in the thymus, we observed that deposits of fibronectin and laminin increased progressively during the course of infection, reaching a maximum at the peak of parasitemia and thymic atrophy. Concomitantly, membrane expression of fibronectin and laminin receptors (VLA-4, VLA-5 and VLA-6) was also enhanced on thymocyte subsets of infected mice. These results correlated with changes in intrathymic thymocyte migration ability during the acute phase of infection, when a higher fibronectin-dependent transmigratory activity of CD4+CD8+ thymocytes was observed. Strikingly, we detected higher frequency of immature and high VLA-expressing CD4+CD8+ T cells in the peripheral lymphoid organs of infected mice at thepeak of parasitemia. These cells seemed to be thymus dependent, since significantly lower amounts of them were found in thymectomized mice, and some of them carry "prohibited" V, segments of the TCR. Our data suggest an imbalance in the intrathymic cell trafficking following acute T. cruzi infection, likely due to dysregulated extracellular matrix-dependent interactions. [source] Major sites for the differentiation of V,14+ NKT cells inferred from the V-J junctional sequences of the invariant T-cell receptor ,,chainFEBS JOURNAL, Issue 1 2001Michio Shimamura CD1d-restricted mouse NK1.1+ TCR,,+ natural killer T (NKT) cells predominantly use an invariant TCR ,,chain encoded by V,14 and J,281 gene segments with a one-nucleotide N region. We found that NKT cells generated in the culture of fetal liver precursors possessed V,14-J,281 junctions that could be produced without the action of terminal deoxyribonucleotidyl transferase (TdT), indicating that NKT cells derived from fetal liver precursors are distinguishable from those from adult precursors with TdT expression. In fact, the frequency of the fetal-form sequences decreased with ageing. Surprisingly, the fetal-type sequences were predominantly observed in the lymphoid organs of athymic mice with the exception of bone marrow, where a sequence peculiar to the organ, with TdT-involved conversion from the invariant junction, was frequently present. These findings suggest that there are two independent sites of V,14+ NKT cell development, the hematopoietic organs throughout life (the developing liver and adult bone marrow) and, principally, the mature thymus. [source] The CD8+ dendritic cell subsetIMMUNOLOGICAL REVIEWS, Issue 1 2010Ken Shortman Summary:, Mouse lymphoid tissues contain a subset of dendritic cells (DCs) expressing CD8, together with a pattern of other surface molecules that distinguishes them from other DCs. These molecules include particular Toll-like receptor and C-type lectin pattern recognition receptors. A similar DC subset, although lacking CD8 expression, exists in humans. The mouse CD8+ DCs are non-migrating resident DCs derived from a precursor, distinct from monocytes, that continuously seeds the lymphoid organs from bone marrow. They differ in several key functions from their CD8, DC neighbors. They efficiently cross-present exogenous cell-bound and soluble antigens on major histocompatibility complex class I. On activation, they are major producers of interleukin-12 and stimulate inflammatory responses. In steady state, they have immune regulatory properties and help maintain tolerance to self-tissues. During infection with intracellular pathogens, they become major presenters of pathogen antigens, promoting CD8+ T-cell responses to the invading pathogens. Targeting vaccine antigens to the CD8+ DCs has proved an effective way to induce cytotoxic T lymphocytes and antibody responses. [source] T-cell receptor proximal signaling via the Src-family kinases, Lck and Fyn, influences T-cell activation, differentiation, and toleranceIMMUNOLOGICAL REVIEWS, Issue 1 2009Robert J. Salmond Summary:, T-cell development in the thymus and activation of mature T cells in secondary lymphoid organs requires the ability of cells to respond appropriately to environmental signals at multiple stages of their development. The process of thymocyte selection insures a functional T-cell repertoire, while activation of naive peripheral T cells induces proliferation, gain of effector function, and, ultimately, long-lived T-cell memory. The T-cell immune response is initiated upon engagement of the T-cell receptor (TCR) and coreceptor, CD4 or CD8, by cognate antigen/major histocompatibility complexes presented by antigen-presenting cells. TCR/coreceptor engagement induces the activation of biochemical signaling pathways that, in combination with signals from costimulator molecules and cytokine receptors, direct the outcome of the response. Activation of the src- family kinases p56lck (Lck) and p59fyn (Fyn) is central to the initiation of TCR signaling pathways. This review focuses on our current understanding of the mechanisms by which these two proteins orchestrate T-cell function. [source] Circuitry of nuclear factor ,B signalingIMMUNOLOGICAL REVIEWS, Issue 1 2006Alexander Hoffmann Summary:, Over the past few years, the transcription factor nuclear factor (NF)-,B and the proteins that regulate it have emerged as a signaling system of pre-eminent importance in human physiology and in an increasing number of pathologies. While NF-,B is present in all differentiated cell types, its discovery and early characterization were rooted in understanding B-cell biology. Significant research efforts over two decades have yielded a large body of literature devoted to understanding NF-,B's functioning in the immune system. NF-,B has been found to play roles in many different compartments of the immune system during differentiation of immune cells and development of lymphoid organs and during immune activation. NF-,B is the nuclear effector of signaling pathways emanating from many receptors, including those of the inflammatory tumor necrosis factor and Toll-like receptor superfamilies. With this review, we hope to provide historical context and summarize the diverse physiological functions of NF-,B in the immune system before focusing on recent advances in elucidating the molecular mechanisms that mediate cell type-specific and stimulus-specific functions of this pleiotropic signaling system. Understanding the genetic regulatory circuitry of NF-,B functionalities involves system-wide measurements, biophysical studies, and computational modeling. [source] Regulatory T cells and intestinal homeostasisIMMUNOLOGICAL REVIEWS, Issue 1 2005Janine L. Coombes Summary:, Murine models of inflammatory bowel disease (IBD) are useful tools for the study of the pathogenesis and regulation of intestinal inflammation. Colitis can be induced in immune-deficient mice following transfer of populations of T cells or following infection with Helicobacter hepaticus and other intestinal pathogens. In these situations, colitis occurs as a result of the absence of a specialized population of regulatory cells, as transfer of CD4+CD25+ T cells prevents disease. Importantly, from a clinical perspective, CD4+CD25+ T cells can also reverse an established colitis. CD4+CD25+ T cells proliferate both in the secondary lymphoid organs and at the site of inflammation, suggesting that regulation occurs both locally and systemically. CD4+CD25+ T cells are not only capable of regulating other T cells but are also capable of suppressing components of the innate immune system. Control of colitis is dependent on the presence of the immunosuppressive cytokines interleukin-10 and transforming growth factor-,, although their roles are divergent and complex. Regulatory T cells represent one of the host's mechanisms to prevent immune pathology during chronic immune stimulation. Enhancement of regulatory T-cell activity may be useful to control autoreactive T-cell responses and inhibit harmful inflammatory diseases such as asthma and IBD. [source] DNA vaccines suppress tumor growth and metastases by the induction of anti-angiogenesisIMMUNOLOGICAL REVIEWS, Issue 1 2004Ralph A. Reisfeld Summary:, Four novel oral DNA vaccines provide long-lived protection against melanoma, colon, breast, and non-small cell lung carcinoma in mouse model systems. The vaccines are delivered by attenuated Salmonella typhimurium to secondary lymphoid organs and are directed against targets such as carcinoembryonic antigen, tyrosine-related protein, vascular endothelial growth factor receptor-2 [also called fetal liver kinase-1 (FLK-1)], and transcription factor Fos-related antigen-1 (Fra-1). The FLK-1 and Fra-1 vaccines are effective in suppressing angiogenesis in the tumor vasculature. All four vaccines are capable of inducing potent cell-mediated protective immunity, breaking peripheral T-cell tolerance against these self-antigens resulting in effective suppression of tumor growth and metastasis. It is anticipated that such research efforts will contribute toward the rational design of future DNA vaccines that will be effective for prevention and treatment of human cancer. [source] Genetic dissection of thymus development in mouse and zebrafishIMMUNOLOGICAL REVIEWS, Issue 1 2003Thomas Boehm Summary:, Lymphoid organs represent a specialized microenvironment for interaction of stromal and lymphoid cells. In primary lymphoid organs, these interactions are required to establish a self-tolerant repertoire of lymphocytes. While detailed information is available about the genes that control lymphocyte differentiation, little is known about the genes that direct the establishment and differentiation of principal components of such microenvironments. Here, we discuss genetic studies addressing the role of thymic epithelial cells (TECs) during thymopoiesis. We have identifed an evolutionarily conserved key regulator of TEC differentiation, Foxn1, that is required for the immigration of prothymocytes into the thymic primordium. Because Foxn1 specifies the prospective endodermal domain that gives rise to thymic epithelial cells, it can be used to identify the evolutionary origins of this specialized cell type. In the course of these studies, we have found that early steps of thymus development in zebrafish are very similar to those in mice. Subsequently, we have used chemical mutagenesis to derive zebrafish lines with aberrant thymus development. Strengths and weaknesses of mouse and zebrafish models are largely complementary such that genetic analysis of mouse and zebrafish mutants may lead to a better understanding of thymus development. [source] Migration of naive, effector and memory T cells: implications for the regulation of immune responsesIMMUNOLOGICAL REVIEWS, Issue 1 2001Jürgen Westermann Summary: T cells play an important role in protective immune responses and in the pathogenesis of many diseases. Understanding the mechanisms regulating their distribution in vivo may therefore be of therapeutic value. Reviewing studies that have followed the migration of labelled naive, effector and memory T cells in healthy animals reveals that all T-cell subsets enter all organs investigated. Within the tissue, two principally different migration patterns can be identified. First, naive and memory T cells accumulate in lymphoid organs for about 48 h after injection, as the time needed for migration through lymphoid organs is longer than through non-lymphoid organs. During this time, surface molecule expression is temporarily modified. These changes are reversed before leaving the lymphoid organs and entering the blood to start a new cycle of migration. Second, effector T cells are evenly distributed throughout the body, and most die in the tissues within 24 h. However, depending on the presence of cytokines, some are able to survive and to proliferate, and thereby accumulate in defined microenvironments of the body. Analysing the principles regulating T-cell migration and survival within the tissue may lead to the development of new options for the treatment of disease. [source] Sphingosine kinase inhibitor suppresses dendritic cell migration by regulating chemokine receptor expression and impairing p38 mitogen-activated protein kinaseIMMUNOLOGY, Issue 4 2007In Duk Jung Summary The migration of dendritic cells (DCs) to secondary lymphoid organs plays a crucial role in the initiation of adaptive immune responses. Although lipopolysaccharide enhances chemokine receptor 7 (CCR7) expression on DCs, the second signal for the migration of DCs toward the chemokine CCL19 remains unknown. In this study, we show that sphingosine kinase inhibitor (SKI) inhibits the migration of DCs toward CCL19 through the down-regulation of CCR7. Inhibition of p38 mitogen-activated protein kinase (MAPK) activation by SKI may be responsible for the SKI-mediated effects on the regulation of chemokine receptor expression. Impairment of DC migration by the inhibition of p38 MAPK and down-regulation of CCR7 expression may contribute to the protective effects of SKI in DC-related disorders. These results suggest that sphingosine kinase-mediated signalling plays a role in the innate and adaptive immune responses by altering DC migration. [source] | ||||||||||||||||