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Dachshund family transcription factor 1 (DACH1) has been shown to exhibit a tumour‐suppressive role in a number of human cancers. However, the role of DACH1 in hypopharyngeal squamous cell carcinoma (HPSCC) and its function in the tumour microenvironment (TME) are still not clear. Crosstalk between cancer cells and tumour‐associated macrophages (TAMs) mediates tumour progression in HPSCC. The expression of DACH1, CD86 and CD163 was detected in 71 matched HPSCC–non‐cancerous tissue pairs using quantitative real‐time polymerase chain reaction and IHC analysis. Cell proliferation, migration and invasion were monitored by colony formation, Transwell and EdU incorporation assays. ChIP‐qPCR and dual‐luciferase reporter assays were applied to verify the targeting relationships between DACH1 and IGF‐1. Stably transfected HPSCC cells were co‐cultured with MΦ macrophages to assess macrophage polarization and secretory signals. DACH1 was decreased in HPSCC tissues and was indicative of a poor prognosis for HPSCC patients. Decreased DACH1 expression in HPSCC was associated with fewer CD86+ TAMs and more CD163+ TAMs. Knockdown of DACH1 inhibited the proliferation, migration and invasion of FaDu cells via Akt/NF‐κB/MMP2/9 signalling. Additionally, DACH1 was found to directly bind to the promoter region of IGF‐1 to downregulate the secretion of IGF‐1, which inhibited TAMs polarization through the IGF‐1R/JAK1/STAT3 axis. Furthermore, in nude mice, the effects of DACH1 inhibition on tumour progression and M2‐like TAMs polarization were confirmed. These findings suggest that IGF‐1 is a critical downstream effector of DACH1 that suppresses cell migration and invasion and inhibits TAMs polarization. DACH1 could be a therapeutic target and prognostic marker for HPSCC. [ABSTRACT FROM AUTHOR]

Mononuclear cell migration across the endothelium and through connective tissue into inflammatory sites is a multi-step process. After adhesion to the endothelium, there is an initial change in shape from spherical to irregular, followed by the migratory phase itself in which the cells constantly change in shape. In this paper we have investigated the possibility that the shape-changing in this latter phase is controlled by serine/threonine phosphorylation. For this purpose, we used a spontaneously shape- changing variant of U937 monocytoid cells as well as human peripheral blood lymphocytes that had been previously activated by anti-CD3. To test the role o f phosphorylation in shape-changing, a wide range of serine/threonine kinase inhibitors was tested, including ML-7, KT5720, KT5823, H7, H8, staurosporine, calphostin C, sphingosine, bisindolylmaleimide, chelerythrine and KN-62. Only those compounds which inhibited protein kinase C prevented lymphocyte and U937 shape-change and transmigration across polycarbonate filters. However, one specific protein kinase C inhibitor, bisindolylmaleimide, stimulated lymphocyte shape-change, [n conclusion, these studies show that activation of a serine/threonine kinase is necessary for the constant shape-changing required for motility of mononuclear cells. The kinase may be a protein kinase C isotype or a closely related enzyme. [ABSTRACT FROM AUTHOR]

The experiments described in this paper have examined the migration of three fluorochrome-labelled T-lymphocyte subsets (CD4+, CD8+ and γδ+T19+) on a single passage from blood to lymph, through prescapular lymph nodes. Lymphocytes obtained from prescapular efferent lymph were labelled in vitro with fluorochrome and returned to the blood of the same animal. Over the next 2 days, lymph was continuously monitored and the cells in all collections, including the one used for intravenous infusion, were phenotyped and analysed by flow cytometry. Significant differences in the subset ratios between the infused, starting population and the recirculated population iodicated that CD4+ and γδ+T19+ lymphocytes are extracted by a resting lymph node at the same rate and that both are extracted at a faster rate than CD8+ lymphocytes. The results presented here also suggest that a unique subset of γδ+T19+ lymphocytes may be present in blood that does not recirculate through peripheral lymph nodes. [ABSTRACT FROM AUTHOR]

This paper described the influence of factor H on the haemolytic activity of the classical C5 convertase. Factor H showed little effect on the interaction of C5 with EACI,4b,2a,3b cells bearing low numbers of C3b sites, but displayed the inhibitory effect on the interaction of C5 with the intermediate cells bearing high numbers of C3b sites. The higher the number of C3b sites on the cells, the greater the degree of the inhibition by factor H. The inhibition by factor H was accompanied by the inhibition of consumption of CS from the fluid phase, indicating that factor H inhibits the activity of CS convertase, not the binding of activated CS to the cells. [ABSTRACT FROM AUTHOR]

The results presented in this paper demonstrate that a mouse IgM monoclonal antibody (T-80) recognizes an antigen on cells of the T-lymphocyte lineage of sheep. However, this antibody does not identify all T cells, as 10-20% of thymocytes and some peripheral-blood T cells are negative. T-80- thymocytes reside in the medulla. The majority of cortical thymocytes are T-80+ and classified as dull cells on the basis of antigen density per cell as measured by flow microfluorometry. In contrast, T-80+ cells in the periphery can be categorized into two populations, i.e., dull cells and bright cells. Suggestive evidence was obtained that bright T-80+ cells are fast recirculating T cells, whereas dull ceils are sessile or less easily mobilizable T cells in the periphery. In foetal environment, over 90% of thymocytes and approximately 5% of spleen cells are T-80+ at 54 days of gestation (gestation period = 150 days), which may indicate that T-cell emigration from the thymus commences well before mid-gestation in sheep. [ABSTRACT FROM AUTHOR]

Presents abstracts of research papers on cellular migration and immunity, published in the December 2002 supplement of 'Immunology.' 'The recruitment of regulatory T cells by chemokines,' by A.G. Betz; 'Mechanisms of inside-out control of adhesion of human granulocytes under static and flow conditions,' by L. Koenderman.

Antigen-dependent migration inhibition factor produced in cultures of mouse lymph node lymphocytes was further characterized. It was found to bind to Concanavalin A and could be eluted by the appropriate sugar. The pi of the activity was found to be between 6-4 and 6.5 by isoelectric focusing. [ABSTRACT FROM AUTHOR]

Summary: Release of granulysin by γδ T cells contributes to tumour cell killing. A cytolytic 9000 MW isoform of granulysin kills tumour cells directly, whereas a 15 000 MW precursor has been hypothesized to cause both the maturation and migration of dendritic cell (DC) populations. Recruiting DC to a tumour is beneficial as these cells initiate adaptive immune responses, which contribute to the eradication of malignancies. In this study, Vδ2+γδ T cells were activated by stimulation of peripheral blood mononuclear cells with zoledronic acid or Bacillus Calmette–Guérin (BCG), or were isolated and cultured with tumour targets. Although a large proportion of resting Vδ2+γδ T cells expressed 15 000 MW granulysin, 9000 MW granulysin expression was induced only after stimulation with BCG. Increased levels of activation and granulysin secretion were also observed when Vδ2+γδ T cells were cultured with the human B‐cell lymphoma line Daudi. High concentrations of recombinant 15 000 MW granulysin caused migration and maturation of immature DC, and also initiated fugetaxis in mature DC. Conversely, low concentrations of recombinant 15 000 MW granulysin resulted in migration of mature DC, but not immature DC. Our data therefore support the hypothesis that Vδ2+γδ T cells can release granulysin, which may modulate recruitment of DC, initiating adaptive immune responses. [ABSTRACT FROM AUTHOR]

Langerhans' cells ( LC) play pivotal roles in skin immune responses, linking innate and adaptive immunity. In aged skin there are fewer LC and migration is impaired compared with young skin. These changes may contribute to declining skin immunity in the elderly, including increased skin infections and skin cancer. Interleukin-1 β ( IL-1 β) and tumour necrosis factor- α ( TNF- α) are mandatory signals for LC migration and previous studies suggest that IL-1 β signalling may be dysregulated in aged skin. Therefore, we sought to explore the mechanisms underlying these phenomena. In skin biopsies of photoprotected young (< 30 years) and aged (> 70 years) human skin ex vivo, we assessed the impact of trauma, and mandatory LC mobilizing signals on LC migration and gene expression. Biopsy-related trauma induced LC migration from young epidermis, whereas in aged skin, migration was greatly reduced. Interleukin-1 β treatment restored LC migration in aged epidermis whereas TNF- α was without effect. In uncultured, aged skin IL-1 β gene expression was lower compared with young skin; following culture, IL-1 β mRNA remained lower in aged skin under control and TNF- α conditions but was elevated after culture with IL-1 β. Interleukin-1 receptor type 2 ( IL1R2) gene expression was significantly increased in aged, but not young skin, after cytokine treatment. Keratinocyte-derived factors secreted from young and aged primary cells did not restore or inhibit LC migration from aged and young epidermis, respectively. These data suggest that in aged skin, IL-1 β signalling is diminished due to altered expression of IL1B and decoy receptor gene IL1R2. [ABSTRACT FROM AUTHOR]

We previously showed alterations in the thymus during experimental infection with Plasmodium berghei. Such alterations comprised histological changes, with loss of cortical–medullary limits, and the intrathymic presence of parasites. As the combination of chemokines, adhesion molecules and extracellular matrix (ECM) is critical to appropriate thymocyte development, we analysed the thymic expression of ECM ligands and receptors, as well as chemokines and their respective receptors during the experimental P. berghei infection. Increased expression of ECM components was observed in thymi from infected mice. In contrast, down-regulated surface expression of fibronectin and laminin receptors was observed in thymocytes from these animals. Moreover, in thymi from infected mice there was increased CXCL12 and CXCR4, and a decreased expression of CCL25 and CCR9. An altered thymocyte migration towards ECM elements and chemokines was seen when the thymi from infected mice were analysed. Evaluation of ex vivo migration patterns of CD4/CD8-defined thymocyte subpopulations revealed that double-negative (DN), and CD4+ and CD8+ single-positive (SP) cells from P. berghei-infected mice have higher migratory responses compared with controls. Interestingly, increased numbers of DN and SP subpopulations were found in the spleens of infected mice. Overall, we show that the thymic atrophy observed in P. berghei-infected mice is accompanied by thymic microenvironmental changes that comprise altered expression of thymocyte migration-related molecules of the ECM and chemokine protein families, which in turn can alter the thymocyte migration pattern. These thymic disturbances may have consequences for the control of the immune response against this protozoan. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Naive T cells have long been thought to recirculate exclusively between secondary lymphoid organs via the lymph and blood. Evidence is now emerging that this view may be too simplistic and that naive T cells routinely traffic through non-lymphoid organs in a manner similar to that of memory T cells, albeit in lower numbers. This represents a fundamental shift in the current paradigm of T-cell migration through different types of tissue. This review summarizes these recent findings, along with the similarities and differences in migratory properties of naive and memory T cells, and discusses how and why naive T cells might access non-lymphoid tissues. [ABSTRACT FROM AUTHOR]

Summary: Crosstalk between the immune system and the nervous system, via neurotransmitters such as dopamine, is increasingly of interest as we begin to learn how lymphocytes in peripheral tissues can both produce and respond to these molecules. This crosstalk can modulate immune responses by influencing the local tissue environment and can, for instance, influence the activation status and migration of T cells. Immune cells also use neurotransmitters to communicate with each other. Understanding how neurotransmitters influence the immune system may provide novel approaches for targeting diseases associated with tissue‐specific inflammation, such as psoriasis. [ABSTRACT FROM AUTHOR]

The immune response of T lymphocytes to pathogens is initiated in draining secondary lymphoid organs, and activated cells then migrate to the site of infection. Thus, control of naïve and regulatory CD4+ T-cell migration is crucial; however, it is poorly understood in physiological and pathological conditions. We found that CD4+ subpopulations displayed characteristic regulator of G-protein signalling (RGS) gene expression profiles. Regulatory T cells express higher levels of RGS1, RGS9 and RGS16 than naïve cells. These genes are up-regulated upon cell activation and their level of expression correlates within vivocell migration. Using parabiosis, we showed that regulatory T lymphocytes migrate less than naïve T cells and that migrant naïve T cells express even lower RGS levels than their static counterparts. Our results show an inverse correlation between the capacity to migrate and the levels of RGS1, RGS9 and RGS16 for both naïve and regulatory T cells. Taken together, these results suggest a role for RGS molecules in chemokine-induced lymphocyte migration and demonstrate the peculiarity of regulatory T cells in terms of phenotype and migration ability, providing new insights into their function. [ABSTRACT FROM AUTHOR]

Dendritic cells (DC) within tissues may acquire and process antigens, carry them into lymph nodes and cluster and activate T cells. The ability of DC to acquire antigen and to migrate to lymph nodes was estimated during marine retroviral infection caused by Rauscher leukaemia virus (RLV). A novel mechanism of inducing immunodeficiency has now been identified. In mice infected with RLV, DC failed to migrate into lymph nodes following exposure of the skin to the contact sensitizer, fluorescein isothiocyanate. RLV infection of a proportion of DC both in skin and lymph nodes, shown by semi-quantitative polymerase chain reaction (PCR) and down-regulation of expression of adhesion molecules (CD54 and CD44) on the surface of Langerhans' cells, may contribute to the described phenomenon. A failure of DC migration could be an important immunosuppressive mechanism of RLV infection in mice and we speculate on a similar role for DC in human immunodeficiency virus-1 (HIV-1) infection in humans. [ABSTRACT FROM AUTHOR]

The development of the intestinal B-cell compartment in C3H/He mice was studied as a function of age by quantification of the number of intestinal immunoglobulin-secreting cells (lg-SC). Before and at weaning, the number of Ig-SC in the small intestine (SI) was below 10³ Ig-SC per SI. During the first few weeks after weaning, this number rose steeply and continued to rise until the mice were about 48 weeks old, when a maximum of more than 25 × 106 Ig-SC per SI was found. After 1 year of age the number of Ig-SC decreased. At all ages, the great majority of Ig-SC in the SI produced IgA. The increase of the number of IgA-SC in the SI after weaning is reflected in the amount of IgA in intestinal secretions measured by ELISA. The number of lg-SC in the SI was compared with the number of IgSC found in spleen, bone marrow, Peyer's patches and mesenteric lymph nodes. Striking differences were observed between the SI and the other organs tested in total number, isotype distribution and kinetics of the increase of Ig-SC during ontogeny. These differences are discussed in relation to the regulation of the immune response in the SI and the migration patterns of lymphocytes in mucosal tissues. [ABSTRACT FROM AUTHOR]

The protease inhibitors, Epsilon Amino Caproic Acid (E.A.C.A.) and Aprotinin were found to significantly increase the inhibition produced by P.P.D. in the Leucocyte Migration Test (L.M.T.). Dose-response curves showed that the most effective concentrations were for E.A.C.A. 0.01 M and Aprotinin 100 I.U./ml. In a series of 29 subjects with a range of Heaf reactivity this finding was consistent providing that there was a significant inhibition to P.P.D. alone. At these concentrations, cell viability was unaffected and the effect of the drugs could be reversed by washing. The exact mode of action of these inhibitors in the L.M.T. requires further elucidation. [ABSTRACT FROM AUTHOR]

Studies the leucocyte migration inhibitory activity in supernatants of cultured human mononuclear cells. Stimulation of leucocytes with mitogens; Rosette formation; Absence of migration inhibitory activity in cultures stimulated by C-3 or Fc-rosette formation.

Delayed skin reactions or peritoneal cell migration inhibition were elicited in guinea-pigs or rats with egg albumin, diphtheria toxoid, or tuberculin-purified protein derivative either separately or with various combinations of two antigens. When the skin reactions or migration inhibition with the component antigens alone were relatively strong, the corresponding combination elicited weaker reactions than calculated assuming that the antigens would add upon each other independently, i.e. the nonspecific phase was limiting the manifestation. When the reactivity to both components was undetectable or very weak, the combination elicited stronger reactions than calculated, implying synergism of antigen recognition. The combinations of two weakly positive or intermediate reactivities were close to the calculated values in both the diameter of erythema, skin thickness and migration percentage. These results may help in assessing the biological significance of findings in delayed hypersensitivity: even minor differences in strong manifestations may mean great differences in terms of specific lymphocytes, while marginal changes of antigen recognition may lead to apparently great changes of manifestation, when very weak reactivities are measured. [ABSTRACT FROM AUTHOR]

Leucocyte migration inhibitory (MI) activity was investigated in vitro in the delayed hypersensitivity reaction induced by intrapleural injection of PPD into FCA-sensitized guinea-pigs. During the initial reaction (6 h) two types of antigen-dependent MI activity were detected in serum and cell-free exudate. One was of high molecular weight and associated with immunoglobulin and the other was of low molecular weight and appeared to be related to so-called 'antigen-dependent MIF'. As the reaction progressed (i.e. 12-24 h), two types of antigendependent MI activity were revealed in exudate, but not in serum. One was high molecular weight and the other was low molecular weight and thought to be related to so-called 'antigen-independent MIF'. Similar experiments were performed on the reverse passive Arthus reaction in the pleural cavity of guinea-pigs. A high molecular weight MI activity was detected in 6-h cell-free exudate and was found to be antigen-independent. 'So-called MIF' was not found in this reaction. [ABSTRACT FROM AUTHOR]

Culture supernatants containing macrophage migration inhibitory factor (MIF) were obtained by incubating lymphocytes of guinea-pigs, immunized with Freund's complete adjuvant (FCA), with tuberculin PPD in vitro. Exposure of normal peritoneal macrophages to MIF-containing supernatants for 2 hours at 37° (pulse exposure), followed by suspension in culture medium and transfer to capillaries, resulted in inhibition of migration in vitro for the next 24 hours. No inhibition was seen when macrophages were incubated with MIF at 4°. On the other hand when exposure to MIF at 4° was followed by incubation of the cells for 2 hours at 37° in culture medium, m the absence of MIF, inhibition of migration was obtained. These results indicate that: (a) macrophages possess a specific receptor able to bind MIF at either 4° or 37°, and (b) inhibition of migration by receptor bound MIF requires a temperature-dependent active process, the nature of which remains unknown. Passage of lymphocytes through columns of glass beads resulted in a population of cells with intact or heightened MIF-forming ability, as assessed by both conventional and pulse exposure techniques. [ABSTRACT FROM AUTHOR]

Histological evidence is presented for distinct, anatomically determined pathways in the spleen for cells in transit between the white pulp and the red pulp prior to entering the draining veins. In rats and mice these appear as narrow channels of lymphocytes which run between both the periarteriolar lymphatic sheath and the red pulp sinuses, and the peripheral white pulp and the red pulp sinuses, crossing the marginal zone in association with fine argentophilic fibres. These marginal zone bridging channels were found to contain labelled T or B cells 4 and 8 hours after injection which suggested that transit was occurring in the direction from white pulp to red pulp rather than the reverse. Additional histological evidence is given to suggest that, after antigenic stimulation, germinal centre dissociation occurs by release of the germinal centre cells towards the periarteriolar lymphatic sheath before they are shed into the red pulp through marginal zone bridges occurring in the periarteriolar region. The data are incorporated into a scheme of unidirectional lymphoid cell flow through the spleen. This proposes that the spleen is composed of many functionally discrete units in which the anatomical matrix, reflected by the reticulin fibre pattern, plays a major role. It further implies that the periarteriolar region of the spleen is not totally thymus dependent. [ABSTRACT FROM AUTHOR]

The purpose of this investigation was to compare and contrast the migratory behaviour of three sub-classes of spleen lymphocytes in the mouse: cells capable of adsorbing a specific labelled antigen on to their surfaces ('antigenbinding' cells); bone-marrow-derived ('B') cells; and thymus-derived ('T') cells. Antigen-binding spleen cells were labelled in vitro with 125l-polymerized flagellin from Salmonella adelaide and injected intravenously into syngeneic recipients. Their distribution within the spleen was studied by radioautography for 24 hours after injection. Nearly all the antigen-binding cells localized and accumulated in and around the germinal centres of the white pulp. Bone-marrow-derived B-spleen cells which were labelled in vitro with ³H-uridine were found to localize in and around germinal centres. The proportion of B cells found in these regions was lower than the proportion of antigen-binding cells and there was not a progressive aggrregation of B cells over 48 hours. Thymus-derived T-spleen cells also labelled in vitro with ³H-uridine were located predominantly in the established thymus-dependent periarteriolar regions of the white pulp. The significance of the localization of antigen-binding cells in the germinal centre regions of spleen is discussed in relation to the B and T components of the spleen lymphocyte population. The conclusion was reached that B lymphoytes activated by contact with antigen Iodged preferentially in germinal centre areas. [ABSTRACT FROM AUTHOR]