pinecone/core-2020-05-10-deduplication huggingface dataset:
Systemic autoimmune disease induced by dendritic cells that have captured necrotic but not apoptotic cells in susceptible mouse strains

Systemic lupus erythematosus (SLE) is an autoimmune disorder of a largely unknown etiology. Anti-double-stranded (ds) DNA antibodies are a classic hallmark of the disease, although the mechanism underlying their induction remains unclear. We demonstrate here that, in both lupus-prone and normal mouse strains, strong anti-dsDNA antibody responses can be induced by dendritic cells (DC) that have ingested syngeneic necrotic (DC/nec), but not apoptotic (DC/apo), cells. Clinical manifestations of lupus were evident, however, only in susceptible mouse strains, which correlate with the ability of DC/nec to release IFN-γ and to induce the pathogenic IgG2a anti-dsDNA antibodies. Injection of DC/nec not only accelerated disease progression in the MRL/MpJ-lpr/lpr lupus-prone mice but also induced a lupus-like disease in the MRL/MpJ-+/+ wild-type control strain. Immune complex deposition was readily detectable in the kidneys, and the mice developed proteinuria. Strikingly, female MRL/MpJ-+/+ mice that had received DC/nec, but not DC/apo, developed a 'butterfly' facial lesion resembling a cardinal feature of human SLE. Our study therefore demonstrates that DC/nec inducing a Th1 type of responses, which are otherwise tightly regulated in a normal immune system, may play a pivotal role in SLE pathogenesis. © 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.postprin
Immunoregulatory role of Jα281 T cells in aged mice developing lupus-like\ud
nephritis.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the emergence of autoreactive T cells. Humans and mice with SLE have reduced numbers of CD1d-restricted invariant natural killer T (iNKT) cells, suggesting a key role for these cells in its immunopathogenesis. This subset uses an invariant TCR constituted by Valpha14 Jalpha281 chains paired with some Vbeta domains. The regulatory role for iNKT cells in non-autoimmune mice was suggested by our previous results showing that aged Jalpha281 knockout (KO) mice produce anti-dsDNA. Here we show that old Jalpha281 KO mice have proteinuria and antibodies against dsDNA and cardiolipin. Histological analysis of Jalpha281 KO mice revealed glomeruli damage and deposition of C3c and IgG, mainly of the IgG3 subclass. In spleens of aged Jalpha281 KO mice there is an increase of activated marginal zone B cells. The evolution of lesions may depend on the age-associated increase of autoantibodies production, preferentially IgG3, mainly secreted by marginal zone B cells. Our results provide the first evidence of a lupus-like syndrome in non-autoimmune mice, supporting an age-related immunoregulatory role of Jalpha281+ cells, probably associated with the activation of marginal zone B cells
Exogenous IFN-γ Ex Vivo Shapes the Alloreactive T-Cell Repertoire by Inhibition of Th17 Responses and Generation of Functional Foxp3+ Regulatory T Cells

Interferon (IFN)-γ was originally characterized as a pro-inflammatory cytokine with T helper type 1-inducing activity, but subsequent work has demonstrated that mice deficient in IFN-γ or IFN-γ receptor show exacerbated inflammatory responses and accelerated allograft rejection, suggesting that IFN-γ also has important immunoregulatory functions. Here, we demonstrate that ex vivo IFN-γ conditioning of CD4 T cells driven by allogeneic immature dendritic cells (DC) results in the emergence of a Foxp3+ regulatory T-cell (Treg)- dominant population that can prevent allograft rejection. The development of this population involves conversion of non-Treg precursors, preferential induction of activation-induced cell death within the non-Treg population and suppression of Th2 and Th17 responses. The suppressive activity of IFN-γ is dependent on the transcription factor signal transducer and activator of transcription 1 and is mediated by induced nitric oxide. These data indicate not only how IFN-γ could be used to shape beneficial immune responses ex vivo for possible cell therapy but also provide some mechanistic insights that may be relevant to exacerbated inflammatory responses noted in several autoimmune and transplant models with IFN-γ deficiency
Migration of antibody secreting cells towards CXCL12 depends on the isotype that forms the BCR

Truncation of the cytoplasmic tail of membrane-bound IgE in vivo results in lower serum IgE levels, decreased numbers of IgE-secreting plasma cells and the abrogation of specific secondary immune responses. Here we present mouse strain KN1 that expresses a chimeric epsilon-gamma1 BCR, consisting of the extracellular domains of the epsilon gene and the transmembrane and cytoplasmic domains of the gamma1 gene. Thus, differences in the IgE immune response of KN1 mice reflect the influence of the "gamma1-mediated signalling" of mIgE bearing B cells. KN1 mice show an increased serum IgE level, resulting from an elevated number of IgE-secreting cells. Although the primary IgE immune response in KN1 mice is inconspicuous, the secondary response is far more robust. Most strikingly, IgE-antibody secreting cells with "gamma1-signalling history" migrate more efficiently towards the chemokine CXCL12, which guides plasmablasts to plasma cell niches, than IgE-antibody secreting cells with WT "epsilon-signalling history". We conclude that IgE plasmablasts have an intrinsic, lower chance to contribute to the long-lived plasma cell pool than IgG1 plasmablasts
Site-specific anti-tumor immunity: differences in DC function, TGF-beta production and numbers of intratumoral Foxp3+ Treg

Gliomas localized within the CNS are generally not rejected by the immune system despite being immunogenic. This failure of the immune system has been associated both with glioma-derived immunosuppressive molecules and the immune-privileged state of the CNS. However, the relative contribution of tumor location to the glioma-mediated immunosuppression, as well as the immune mechanisms involved in the failure of glioma rejection are not fully defined. We report here that syngeneic GL261 gliomas growing either intracranially or subcutaneously in mice are infiltrated by DC and T cells. However, only subcutaneous gliomas elicit an effective anti-tumor immune response. In contrast to DC infiltrating subcutaneously grown GL261 gliomas, tumor-infiltrating DC from intracranial gliomas do not activate antigen-dependent T-cell proliferation in vitro. In addition, brain-localized GL261 gliomas are characterized by significantly higher numbers of Foxp3(+) Treg and higher levels of TGF-beta1 mRNA and protein expression when compared with GL261 gliomas in the skin. Our data show that gliomas in the CNS, but not in the skin, give rise to TGF-beta production and accumulation of both Treg and functionally impaired DC. Thus, not the tumor itself, but its location dictates the efficiency of the anti-tumor immune response
Natural killer cells become tolerogenic after interaction with apoptotic cells

NK cells are effectors in innate immunity and also participate in immunoregulation through the release of TGF-β1 and lysis of activated/autoreactive T cells. Apoptotic cells (AC) have been shown to induce tolerogenic properties in innate immune cells, including macrophages and dendritic cells, but not NK cells. In this study, we demonstrated that after interaction with AC, NK cells released TGF-β1, which in turn suppressed the production of IFN-γ by NK cells upon IL-12 and IgG activation.We further identified phosphatidylserine as a potential target on AC for the NK cells, as phosphatidylserine could stimulate NK cells to release TGF-β1, which in turn suppressed CD4+ T-cell proliferation and activation. Moreover, AC-treated NK cells displayed cytotoxicity against autologous-activated CD4 + T cells by upregulating NKp46. This lysis occurred in part through the NKp46-vimentin pathway, as activated CD4+ T cells expressed vimentin on the cell surface and blocking of vimentin or NKp46, but not other NK-cell receptors, significantly suppressed the NK-cell cytotoxicity.We report here a novel interaction between NK cells and AC, resulting in the tolerogenic properties of NK cells required for immune contraction. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.postprin
GITR contributes to the systemic adjuvanticity of the Escherichia coli heat-labile enterotoxin

El pdf del artículo es el manuscrito de autor.-- et al.The Escherichia coli heat-labile enterotoxin (LT) possesses a powerful mucosal and systemic adjuvant effect. However, little is known about the cellular and molecular basis of the immunostimulatory activity of LT at the mucosal level, and even less information is available on the mechanisms underlying its systemic adjuvant activity. In this study, we show that distinct mechanisms are responsible for the parenteral and mucosal adjuvanticity of LT. Indeed, the systemic administration of LT upregulates the expression of glucocorticoid-induced TNFR-related protein (GITR), but not other activation markers, in naive T cells. Using WT and GITR-deficient mice and LT and its enzymatically inactive mutant LTK63 as adjuvants, we show that the induction of GITR expression in T cells accounts for the systemic immunostimulatory capacity of LT, which requires an intact enzymatic activity. In contrast, the mucosal administration of LT does not induce GITR expression on Peyer's patche T cells and accordingly no differences are observed in the mucosal adjuvanticity of LT between WT and GITR-deficient mice. Altogether, our results demonstrate the distinct effect of LT after parenteral administration when compared with the mucosal delivery, and describe a new mechanism of LT adjuvanticity related to its ability to induce the expression of GITR in CD4+ T cells.This work was supported by grants from the Ministerio de Educación y Ciencia, Spain\ud
to RM (SAF2008-02042) and JM (SAF2006-12520-C02-02\ud
and BFU2009-07206), from the Fundación Marqués de\ud
Valdecilla, Spain to JM (API-07/02), by a research agreement sponsored by Novartis Vaccines and Diagnostics (to R. M. and J. M.), by grant REDINREN RD06/0016 from the ‘‘Instituto de Salud Carlos III’’ to R. M. and by grant no LSHP-CT-\ud
2003–503240 (MUVAPRED, Mucosal Vaccines for Poverty Related Diseases) from the ‘‘European Commission’’ to G. D. G. and R. R.Peer reviewe
Dichotomy between factors inducing the immunosuppressive enzyme IL-4-induced gene 1 (IL4I1) in B lymphocytes and mononuclear phagocytes.

International audienceMPhi and DC are key elements in the control of tissue homeostasis and response to insult. In this work, we demonstrate that MPhi and DC are the major producers of the phenylalanine catabolizing enzyme IL-4-induced gene 1 (IL4I1) under inflammatory conditions. IL4I1 was first described in B cells, which indeed can produce IL4I1 in vitro, although at much lower levels. In vivo, IL4I1 is highly expressed by MPhi and DC of Th1 granulomas (sarcoidosis, tuberculosis) but poorly detected in Th2 granulomas (schistosomiasis). In vitro, expression of the enzyme is induced in mononuclear phagocytes by various pro-inflammatory stimuli through the activation of the transcription factors NF-kappaB and/or STAT1. B cells also express IL4I1 in response to NF-kappaB-activating stimuli such as CD40L; however, in contrast to myeloid cells, B cells are insensitive to IFN-gamma but respond to stimulation of the IL-4/STAT6 axis. As we show that the expression of IL4I1 by a monocytic cell line inhibits T-cell proliferation and production of IFN-gamma and inflammatory cytokines, we propose that IL4I1 participates in the downregulation of Th1 inflammation in vivo
Increased CD127 expression on activated FOXP3+CD4+ regulatory T cells.

International audienceRegulatory T cells (Treg) are commonly identified by CD25 (IL-2R alpha) surface expression and/or intracellular expression of the FOXP3 transcription factor. In addition, Treg are also characterized by low CD127 (IL-7R alpha) expression when compared to conventional T cells and their biology in the periphery is considered essentially independent of IL-7. We further investigated CD127 expression on Treg and we demonstrated differential CD127 expression depending on Treg subsets considered. Notably, we observed high CD127 expression on inducible costimulatory molecule (ICOS)- and CD103-expressing Treg subsets. Since these two markers reflect activation status, we addressed whether Treg activation modulated CD127 expression. We demonstrated that in contrast to conventional T cells, Treg significantly upregulated CD127 expression during in vitro and in vivo activation using adoptive transfer and contact dermatitis models. High CD127 expression on Treg was also predominantly detected ex vivo in some specific sites, notably bone marrow and skin. Importantly, higher CD127 expression on Treg correlated with higher phosphorylation of STAT5 upon IL-7 exposure. High CD127 expression on Treg also provided survival advantage upon in vitro incubation with IL-7. We thus demonstrated that low CD127 expression is not an intrinsic characteristic of Treg and we identified activated Treg as a potential target of endogenous or therapeutic IL-7
The role of dendritic cells in adjuvant-induced immune responses

Dendritic cells (DCs) are sentinels of mucosal surfaces, residing directly under the epithelial layer. DCs are among the first cells that come in contact with pathogens and have the unique ability to activate T cells that subsequently can aid B cells to produce antibodies with high affinity. T and B cells constitute our immunological memory that protects us from reinfections – the basis for vaccination. Vaccines composed of purified antigens, confer high specificity but have low intrinsic immunogenicity, and require therefore an adjuvant that enhances the response. The most potent adjuvants are often toxic, and consequently a limited number of adjuvants are available for clinical use, mucosal adjuvants in particular. Therefore, a better understanding is needed concerning the interactions between adjuvants and DCs in order to unveil the mechanisms of adjuvanticity. Here we have in vivo studied the role of DCs and the characteristics of the immune response after immunization with different adjuvants.

Adenoviral (Ad) vaccine vectors inducing expression of ovalbumin (OVA) at different subcellular locations were used in a mouse model in which conventional DCs (cDCs) could be depleted. We show that cDCs are required for activation of T cells although a direct transduction of cDCs by Ad-vectors is not essential. Further we determine that secreted and membrane-anchored antigens are superior at activating antigen-specific CD4+, cytotoxic CD8+ T lymphocytes as well as generating a serum IgG response compared to intracellulary expressed OVA. 
Cholera toxin (CT) is one of the most potent mucosal adjuvants. CT binds the ubiquitously expressed ganglioside GM1 leading to efficient uptake that in epithelial cells results in secretion of fluid into the lumen. After oral immunization with OVA and CT we find that chimeric mice lacking GM1 on hematopoietic cells, and specifically GM1-expressing DCs, fail to induce adaptive immune responses to OVA. We conclude that CT does not require the toxic epithelial cell interaction for its adjuvant activity but is dependent on direct binding of GM1 on intestinal DCs.
To become plasma cells producing high affinity antibodies, B cells must undergo affinity maturation in the germinal center where they are dependent on the help of follicular helper T cells. In DC-depleted mice, we show that immunization with the adjuvant poly(I:C) and non-limiting doses of OVA generates follicular T helper cells (Tfh) and germinal centers in absence of DCs. In contrast, B cell interactions are required for a fully differentiated Tfh phenotype and the activation of a Th1 mediated T cell response is totally dependent on DCs. 

Strategies targeting vaccine antigens to DCs are becoming more promising as novel DC-specific receptors are being discovered. Taken together our results show great heterogeneity concerning the role of DCs in adjuvant-induced immune responses. How to modulate and take advantage of the interactions between adjuvants and DCs will be crucial knowledge in the construction of future more effective and safe vaccines
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IL4I1 and tumor immunoresistance

International audienceThe L-phenylalanine oxidase IL4I1 inhibits T-cell proliferation in vitro through H(2) O(2) production, and is highly expressed in tumor-associated macrophages. IL4I1 is also detected by immunohistochemistry in neoplastic cells from several B-cell lymphomas and some non-lymphoid tumors. To evaluate IL4I1's effect on tumor growth, we developed a mouse melanoma model constitutively coexpressing IL4I1 and the GP33 epitope. After GP33 vaccination, tumors developed more frequently in mice injected with IL4I1-expressing cells in comparison with mice receiving control cells. Tumor escape was preceded by a rapid diminution of IFN-γ-producing cytotoxic antitumor CD8(+) T cells. Moreover, tumor incidence was already increased when only 20% of the injected cells expressed IL4I1. The minimal IL4I1 activities leading to tumor escape were close to those detected in human melanoma and mesothelioma. Thus, we demonstrate the immunosuppressive functions of IL4I1 in vivo and suggest that IL4I1 facilitates human tumor growth by inhibiting the CD8(+) antitumor T-cell response
Differential role for CD277 as a co-regulator of the immune signal in T and NK cells.

International audienceThe human butyrophilin (BTN) 3 or CD277 molecules belong to the B7 family members and are expressed in various immune cells such as T and NK cells. Here, we show that CD277 triggering considerably enhances TCR-induced cytokine production and cell proliferation, even when another co-stimulatory molecule, CD28, is engaged. These CD277-induced additive functional effects are in accordance with the detection of early T-cell activation events such as TCR-induced cell signaling being increased upon CD277 engagement. However, we found that CD277 triggering is not involved in CD16- or NKp46-induced NK cell activation. BTN3/CD277 comprises three structurally related members, BTN3A1, BTN3A2 and BTN3A3. CD277 antibodies recognize all isoforms and we describe a differential expression of BTN3 isoforms between T and NK cells that could explain differential CD277 functions between T and NK cells. Our results show that, while T cells express all BTN3/CD277 transcripts, NK cells express mostly BTN3A2, which lacks the B30.2 intracellular domain. Furthermore, NKp30-induced cytokine production is decreased by the specific engagement of BTN3A2, but not by BTN3A1 triggering. Thus, we provide new insights into the CD277 co-stimulatory pathway that may differentially participate in the regulation of various cell-mediated immune responses
Lack of IL‐7 and IL‐15 signaling affects interferon‐γ production by, more than survival of, small intestinal intraepithelial memory CD8 +  T cells

Survival of antigen‐specific CD8 +  T cells in peripheral lymphoid organs during viral infection is known to be dependent predominantly on IL‐7 and IL‐15. However, little is known about a possible influence of tissue environmental factors on this process. To address this question, we studied survival of memory antigen‐specific CD8 +  T cells in the small intestine. Here, we show that 2 months after vaccinia virus infection, B8R 20–27 /H2‐K b  tetramer +  CD8 +  T cells in the small intestinal intraepithelial (SI‐IEL) layer are found in mice deficient in IL‐15 expression. Moreover, SI‐IEL and lamina propria lymphocytes do not express the receptor for IL‐7 (IL‐7Rα/CD127). In addition, after in vitro stimulation with B8R 20–27  peptide, SI‐IEL cells do not produce high amounts of IFN‐γ neither at 5 days nor at 2 months postinfection (p.i.). Importantly, the lack of IL‐15 was found to shape the functional activity of antigen‐specific CD8 +  T cells, by narrowing the CTL avidity repertoire. Taken together, these results reveal that survival factors, as well as the functional activity, of antigen‐specific CD8 +  T cells in the SI‐IEL compartments may markedly differ from their counterparts in peripheral lymphoid tissues
Palmitoylation of MICA, a ligand for NKG2D, mediates its recruitment to membrane microdomains and promotes its shedding

S. Agüera-González... et al.MICA and MICB (MHC-class-I-related chain A/B) are transmembrane proteins expressed in pathological conditions that are ligands for NKG2D, an activating receptor found on cytotoxic lymphocytes. The recognition on target cells of NKG2D ligands leads to the activation of lysis and cytokine secretion by NK cells and T cells. Besides being expressed at the cell surface, MICA/B can be released as soluble proteins. Soluble NKG2D ligands downmodulate expression of the NKG2D receptor on lymphocytes, leading to a diminished cytotoxic response. Prior studies suggested that recruitment of MICA/B molecules to cholesterol-enriched microdomains was an important factor regulating the proteolytic release of these molecules. We now show that recruitment of MICA to these microdomains depends on palmitoylation of two cysteine residues that allow MICA molecules to reside in the membrane in the same domains as caveolin-1. Compared with WT molecules, nonpalmitoylated mutant MICA molecules were shed to the supernatant with low efficiency; however, both WT and mutant MICA were able to trigger NK cell cytotoxicity. These data suggest that the presence of NKG2D ligands at the plasma membrane is sufficient to activate cytotoxicity and reflect the need of different ligands to exploit different cellular pathways to reach the cell surface upon different stress situations.The authors would like to thank Nigel Miller for assistance with cell sorting. This work was\ud
supported by grants from the Medical Research Council (New Investigator Grant to MVG)\ud
and Fondo de Investigación Sanitaria (PS09/00181 and PI08/1701) and, in part, by the\ud
Intramural Research Program of the National Institutes of Health, National Institute of Allergy\ud
and Infectious Diseases. OA was supported by the Leukaemia Research Fund and The\ud
Newton Trust. HCH was supported by grants from Ellison Medical Foundation and\ud
NIH/NIGMS GM087544. SA was a recipient of a short-term fellowship from the European\ud
Molecular Biology Organization and supported in part by fellowships from Caja Madrid and\ud
Ibercaja.Peer reviewe
Affinity maturation of antibodies requires integrity of the adult thymus

The generation of B‐cell responses to proteins requires a functional thymus to produce CD4 +  T cells which helps in the activation and differentiation of B cells. Because the mature T‐cell repertoire has abundant cells with the helper phenotype, one might predict that in mature individuals, the generation of B‐cell memory would proceed independently of the thymus. Contrary to that prediction, we show here that the removal of the thymus after the establishment of the T‐cell compartment or sham surgery without removal of the thymus impairs the affinity maturation of antibodies. Because removal or manipulation of the thymus did not decrease the frequency of mutation of the Ig variable heavy chain exons encoding antigen‐specific antibodies, we conclude that the thymus controls affinity maturation of antibodies in the mature individual by facilitating the selection of B cells with high‐affinity antibodies