European Journal of Immunology
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Kynurenine 3‐monooxygenase mediates inhibition of <scp>T</scp>h17 differentiation via catabolism of endogenous aryl hydrocarbon receptor ligands The aryl hydrocarbon receptor (A hR ) is a key transcriptional regulator of T h17‐cell differentiation. Although endogenous ligands have yet to be identified, evidence suggests that tryptophan metabolites can act as agonists for the A hR . Tryptophan metabolites are abundant in circulation, so we hypothesized that cell intrinsic factors might exist to regulate the exposure of T h17 cells to A hR ‐dependent activities. Here, we find that T h17 cells preferentially express kynurenine 3‐monooxygenase (KMO ), which is an enzyme involved in catabolism of the tryptophan metabolite kynurenine. KMO inhibition, either with a specific inhibitor or via siRNA ‐mediated silencing, markedly increased IL ‐17 production in vitro, whereas IFN ‐γ production by T h1 cells was unaffected. Inhibition of KMO significantly exacerbated disease in a T h17‐driven model of autoimmune gastritis, suggesting that expression of KMO by T h17 cells serves to limit their continuous exposure to physiological levels of endogenous A hR ligands in vivo.
European Journal of Immunology - Tập 43 Số 7 - Trang 1727-1734 - 2013
Virgin B cell recruitment and the lifespan of memory clones during antibody responses to 2,4‐dinitrophenyl‐hemocyanin Abstract The extent to which B cells newly formed in the bone marrow contribute to primary and secondary B cell responses was investigated. This was assessed by constructing chimeras between congenic strains of rats differing in their kappa light chain allotype. Recipient animals received 800 cGy whole body irradiation with hind limb shieldin to protect a proportion of their hemopoietic capacity. These rats then received 3 × 108 kappa allotype‐marked thoracic duct lymphocytes from donors previously immunized twice with either dinitrophenylated spider crab (Maia squinada ) hemocyanin (DNP‐MSH) or MSH alone. The chimeras were immunized with DNP‐MSH and the production of anti‐DNP antibody of both donor and host origin was measured. In the period immediately after immunization both newly formed host virgin B cells and donor memory B cells gave rise to substantial proportions of the anti‐DNP antibody. After this initial period, antibody production became sustained by activation of memory B cells only. The chimeras were reimmunized with DNP‐MSH at 32 days after their first immunization. There was again evidence of a brief period of both virgin and memory B cell activation followed by memory B cell activation only. Donor B cell clones remained dominant in the established response throughout the 5 months each chimera was studied. The data are interpreted as indicating two phases of B cell activation. It is suggested that the first phase where both virgin and memory B cells are activated may be associated with antigen presentation on dendritic or interdigitating cells outside follicles. It is argued that the second phase where only memory B cells are activated is more likely to be associated with antigen on follicular dendritic cells.
European Journal of Immunology - Tập 16 Số 6 - Trang 641-648 - 1986
The carrier effect in the secondary response to hapten‐protein conjugates. II. Cellular cooperation Abstract The adoptive secondary response of mice to conjugates of NIP (4‐hydroxy‐5‐iodo‐3‐nitro‐phenacetyl‐) and DNP (2,4‐dinitrophenyl‐) is here used to elucidate the mechanism of cellular cooperation. The framework into which the experiments fit can be formulated as follows. Priming immunization raises a crop not only of specific antibody‐forming‐cell‐precursors (AFCP) but also of specific helper cells. Upon secondary stimulation the helper cells serve a role as handlers or concentrators of antigen, thus enabling AFCP which would otherwise be incapable of reacting to initiate antibody synthesis. In this act of cooperation both cells recognise antigen; in the system examined here the helpers recognise carrier determinants and the AFCP recognise either the hapten or other carrier determinants. The first aim of the experiments was to raise populations of helpers and AFCP of distinguishable specificity. Mice were primed with NIP‐Ovalbumin (OA) mixed with chicken γ‐globulin (CGG) and bovine serum albumin (BSA); in comparison with controls primed with unmixed NIP‐OA, their cells after transfer were relatively more sensitive to secondary stimulation with NIP‐CGG or NIP‐BSA and similar findings were obtained in cross‐checks of these carriers. For reasons which are not entirely clear, non‐transferred cells did not show the same effect. In further experiments cells primed with one conjugate (e. g. NIP‐OA) were mixed with cells primed with another protein (e. g. BSA), transferred and challenged with the hapten conjugated to the second protein (i. e. NIP‐BSA). In comparison with controls lacking the protein‐primed cells, the mixture regularly showed greater sensitivity to stimulation. NIP and DNP were tested in many of the possible combinations with BSA, OA and CGG with the same result. The mixture system was used in the further analysis. Tests with allotype‐marked protein‐primed cells showed that these cells did not participate in the production of the anti‐hapten antibody and could therefore properly be regarded as helpers. Tests of specificity showed that physical union of the hapten and carrier were required: cells primed with BSA, for example, would not help NIP‐OA‐primed cells to make a response to NIP‐HSA even when stimulated at the same time with BSA. Transfer of less than one‐tenth of the spleen gives a maximum helper effect, whereas AFCP activity continues to rise as larger numbers of cells are transferred. Helper cells are therefore normally present in excess. Helper activity is more resistant than AFCP activity to irradiation, drugs and semi‐allogeneic cell transfer across an H‐2 barrier. This suggests that helper cells play a relatively passive role in the immune response. Several observations indicate that helper cells are thymus‐derived mediators of cellular immunity. Passively transferred antibody did not substitute for helper cells. After immunization helper activity developed faster than AFCP activity. Spleen cells obtained from lethally‐irradiated, thymocyte‐repopulated, immunized donors provided help. Cells from the thymus‐derived fraction of thymus/marrow chimeras also appear to provide help. Thus, the hapten‐carrier cooperative response maps onto the well‐established synergy of thymus and marrow in the response to foreign erythrocytes.
European Journal of Immunology - Tập 1 Số 1 - Trang 18-27 - 1971
Pertussis toxin as an adjuvant suppresses the number and function of CD4<sup>+</sup>CD25<sup>+</sup> T regulatory cells Abstract We observed a remarkable reduction in the frequency and immunosuppressive activity of splenic CD4+ + 33–55 ‐induced experimental autoimmune encephalomyelitis (EAE). Our study revealed that pertussis toxin (PTx), one component of the immunogen used to induce murine EAE, was responsible for down‐regulating splenic CD4+ + in vivo reduced the frequency, suppressive activity and FoxP3 expression by splenic CD4+ + + + + + in vitro , but did so in vivo , presumably due to an indirect effect. Although the exact molecular target of PTx that reduces Treg activity remains to be defined, our data suggests that alteration of both distribution and function of splenic immunocytes should play a role. This study concludes that an underlying cause for the immunological adjuvanticity of PTx is down‐regulation of Treg cell number and function.
European Journal of Immunology - Tập 36 Số 3 - Trang 671-680 - 2006
Cytotoxicity and immunocyte markers in cells from the freshwater snail <i>Planorbarius corneus</i> (L.) (<i>Gastropoda pulmonata</i>): implications for the evolution of natural killer cells Abstract The hypothesis that natural killer (NK) cells represent an important form of cell recognition and cytotoxicity leads to the prediction that NK‐like activity should be preserved throughout phylogenetic development. This was tested in the invertebrate Planorbarius corneus. Two types of cells can be identified and separated from the hemolymph of this mollusc, i.e. glass‐adherent macrophage‐like spreading hemocytes (SH) and nonadherent round hemocytes (RH). Only RH are able to lyse the K‐562 human target cell line in a short‐term NK cytotoxicity test. This NK‐like activity, severely reduced after 18 h incubation at 24 °C, is preserved by human recombinant interleukin 2. A further analysis of P. corneus hemocytes has been performed by using several mouse anti‐human monoclonal antibodies and cytofluorimetric analysis. Unexpectedly, both SH and RH react with several monoclonal antibodies, including those directed against epitopes typical of mammalian NK cells and cell adhesion molecules. On the whole, these data support the hypothesis that a primitive NK‐like activity appeared early in evolution and is not shared by phagocytic cells.
European Journal of Immunology - Tập 21 Số 2 - Trang 489-493 - 1991
Studies on sperm antigenicity. I. Delayed hypersensitivity to spermatozoa Abstract Delayed hypersensitivity to human and guinea pig sperm was demonstrated in guinea pigs of the Rockefeller strain by immunization with H37 Ra adjuvant. The reaction in vivo was demonstrated by skin testing the animals and in vitro by the capillary method. It was found that the sensitivity is not only directed towards the sensitizing antigen, but also shows cross‐reactivity. Thus, peritoneal exudate cells derived from guinea pigs sensitized to human sperm were inhibited by guinea pig sperm. This cross‐reactivity revealed the possibility of a tissue specific antigen. In addition, supernatants obtained after incubation of the sensitized lymph node cells with the specific antigen were found to be spermatotoxic.
European Journal of Immunology - Tập 3 Số 2 - Trang 75-78 - 1973
<i>Schistosoma mansoni</i> antigens modulate the activity of the innate immune response and prevent onset of type 1 diabetes Abstract Infection with Schistosoma mansoni (S. mansoni ) or exposure to eggs from this helminth inhibits the development of type 1 diabetes in NOD mice. In this study we show that soluble extracts of S. mansoni worm or egg completely prevent onset of type 1 diabetes in these mice but only if injection is started at 4 weeks of age. T cells from diabetes‐protected mice make IL‐10 in recall responses to parasite antigens. These cells are furthermore impaired in their ability to transfer diabetes to NOD‐SCID recipients. Bone marrow dendritic cells derived from NOD mice are found to make more IL‐10 and less IL‐12 following culture with S. mansoni soluble egg antigens in conjunction with lipopolysaccharides. NOD mice are deficient in NKT cells. Soluble worm and egg antigens increase the numbers of Vα14i NKT cells in NOD mice. These effects of schistosome antigens on the innate immune system provide a mechanism for their ability to prevent type 1 diabetes in NOD mice.
European Journal of Immunology - Tập 33 Số 5 - Trang 1439-1449 - 2003
Interleukin‐10 and interleukin‐4 inhibit intracellular killing of <i>Leishmania infantum</i> and <i>Leishmania major</i> by human macrophages by decreasing nitric oxide generation Abstract The host response to Leishmania infection is regulated by a specific pattern of local cytokine production. We investigated the effect of interleukin (IL)‐10 and IL‐4 on the leishmanicidal activity of human macrophages (Mϕ). As with L. major , intracellular killing of L. infantum by human Mϕ was obtained following ligation of surface CD23 or cell treatment with Interferon‐γ (IFN‐γ). This leishmanicidal activity required nitric oxide (NO) generation by activated Mϕ, and it was partially mimicked by cell treatment with chemical NO donors. Addition of recombinant human IL‐10 or IL‐4 to CD23 mAb or IFN‐γ decreased L. infantum and L. major killing by infected Mϕ. IL‐10 was more potent than IL‐4 in inhibiting the leishmanicidal activity of human Mϕ. Inhibition of Leishmania killing by IL‐4 and IL‐10 correlated with decreased NO generation from Mϕ, and was reversed when exogenous NO was added to cell cultures. Therefore, IL‐10 and IL‐4 down‐regulate leishmanicidal activity of human Mϕ, in part by inhibiting NO generation by these cells.
European Journal of Immunology - Tập 27 Số 4 - Trang 860-865 - 1997
Chronic relapsing experimental autoimmune encephalomyelitis (CREAE) in mice: enhancement by monoclonal antibodies against interferon‐γ Abstract Experimental autoimmune encephalomyelitis (EAE) is a T cell‐mediated inflammatory and demyelinating disorder of the central nervous system. Depending on the experimental conditions, it takes an acute monophasic or a chronic relapsing‐remitting course. We have previously reported that the incidence and severity of acute EAE in mice are reduced by administration of interferon (IFN)‐γ and augmented by treatment with neutralizing antibodies against IFN‐γ. Here, we investigated the role of IFN‐γ in chronic relapsing models of EAE (CREAE) in SJL/J and Biozzi ABH mice. Spontaneous relapses in Biozzi mice as well as induced relapses in SJL/J mice were facilitated by administration of neutralizing monoclonal antibody (mAb) against IFN‐γ in the disease‐free interval. The enhancing effect of anti‐IFN‐γ mAb given before and during the primary attack did not carry over to the relapses. However, early administration of IFN‐γ in Biozzi mice, which developed spontaneous relapses in a high proportion, provided partial protection not only against the first attack, but also against subsequent relapses. Administration of exogenous IFN‐γ during the remission phase provided some protection against subsequent relapses. These results indicate that in both types of relapses, IFN‐γ is produced and does provide a certain degree of protection against disease progression.
European Journal of Immunology - Tập 26 Số 10 - Trang 2393-2398 - 1996
Essential requirement for polypyrimidine tract binding proteins 1 and 3 in the maturation and maintenance of mature B cells in mice Abstract The maturation of immature B cells and the survival of mature B cells is stringently controlled to maintain a diverse repertoire of antibody specificities while avoiding self‐reactivity. At the molecular level this is regulated by signaling from membrane Ig and the BAFF‐receptor that sustain a pro‐survival program of gene expression. Whether and how posttranscriptional mechanisms contribute to B cell maturation and survival remains poorly understood. Here, we show that the polypyrimidine tract binding proteins (PTBP) PTBP1 and PTBP3 bind to a large and overlapping set of transcripts in B cells. Both PTBP1 and PTBP3 bind to introns and exons where they are predicted to regulate alternative splicing. Moreover, they also show high‐density of binding to 3’ untranslated regions suggesting they influence the transcriptome in diverse ways. We show that PTBP1 and PTBP3 are required in B cells beyond the immature cell stage to sustain transitional B cells and the B1, marginal zone and follicular B cell lineages. Therefore, PTBP1 and PTBP3 promote the maturation of quiescent B cells by regulating gene expression at the posttranscriptional level.
European Journal of Immunology - Tập 51 Số 9 - Trang 2266-2273 - 2021
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