RESUMEN
Pathophysiologic function of B cells in graft rejection has been well recognized in transplantation. B cells promote alloantigen-specific T-cell response and secrete antibodies that can cause antibody-mediated graft failures and rejections. Therefore, strategies targeting B cells, for example, B-cell depletion, have been used for the prevention of both acute and chronic rejections. Interestingly, however, recent mounting evidence indicates that subsets of B cells yet to be further identified can display potent immune regulatory functions, and they contribute to transplantation tolerance and operational tolerance in both experimental and clinical settings, respectively. In this review, we integrate currently available information on B-cell subsets, including T-cell Ig domain and mucin domain 1-positive transitional and T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domain-positive memory B cells, displaying immune regulatory functions, with a focus on transplantation tolerance, by analyzing their mechanisms of action. In addition, we will discuss potential T-cell Ig domain and mucin domain 1-positive and T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domain-positive B cell-based strategies for the enhancement of operational tolerance in transplantation patients.
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Plasmacytoid dendritic cells (pDC) are the major producer of type 1 IFN in response to TLR7 agonists. Aberrant TLR7 activation and type 1 IFN expression by pDCs are linked to the pathogenesis of certain types of autoimmune diseases, including systemic lupus erythematosus (SLE). This study investigated the underlying mechanisms for TLR7-mediated cytokine expression by pDCs using a late endosome trafficking inhibitor, EGA (4-bromobenzaldehyde N-(2,6-dimethylphenyl) semicarbazone). We found that EGA treatment decreased IFNα expression by pDCs stimulated with imiquimod (R837), single-stranded RNA40, and influenza virus. EGA also decreased TNFα expression and secretion by R837-stimulated pDCs. Mechanistically, EGA treatment decreased phosphorylation of IKKα/ß, STAT1, and p38, and prolonged degradation of IκBα. Furthermore, EGA treatment decreased the colocalization of 3F, a substituted adenine TLR7 agonist, with LAMP1+ compartments in pDCs. EGA was also capable of diminishing IFNα expression by SLE pDCs treated with R837 or live PR8/A/34 influenza viruses. Therefore, we concluded that trafficking of TLR7 agonists to LAMP1+ compartments is important for IFNα expression by pDCs. Data from this study support additional examinations of the potential benefits of EGA in treating type 1 IFN-associated inflammatory diseases in the future.
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Lupus Eritematoso Sistémico , Receptor Toll-Like 7 , Humanos , Receptor Toll-Like 7/metabolismo , Imiquimod , Células Dendríticas , Citocinas/metabolismoRESUMEN
Expression of macrophage receptor with collagenous structure (MARCO) by tumor-associated macrophages is associated with poor prognosis of multiple types of cancer. In this article, we report that cancer cells (e.g., breast cancer and glioblastoma cell lines) can upregulate surface MARCO expression on human macrophages not only via IL-6-induced STAT3 activation but also via sphingosine-1-phosphate receptor (S1PR)-mediated IL-6 and IL-10 expression followed by STAT3 activation. We further found that MARCO ligation induces activation of the MEK/ERK/p90RSK/CREB signaling cascade, leading to IL-10 expression followed by STAT3-dependent PD-L1 upregulation. Such MARCO-induced macrophage polarization is accompanied by increased expression of PPARG, IRF4, IDO1, CCL17, and CCL22. Ligation of surface MARCO can thus result in decreased T cell responses mainly by reduction of their proliferation. Taken together, cancer cell-induced MARCO expression and its intrinsic regulatory function within macrophages are, to our knowledge, new aspects of cancer immune evasion mechanisms that need to be further studied in the future.
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Interleucina-10 , Neoplasias , Humanos , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Macrófagos , Neoplasias/metabolismo , Receptores Inmunológicos , Receptores Depuradores/metabolismoRESUMEN
Plasmacytoid dendritic cells (pDCs) exhibit bifurcated cytokine responses to TLR9 agonists, an IRF7-mediated type 1 IFN response or a pro-inflammatory cytokine response via the activation of NF-κB. This bifurcated response has been hypothesized to result from either distinct signaling endosomes or endo-lysosomal trafficking delay of TLR9 agonists allowing for autocrine signaling to affect outcomes. Utilizing the late endosome trafficking inhibitor, EGA, we assessed the bifurcated cytokine responses of pDCs to TLR9 stimulation. EGA treatment of pDCs diminished both IFNα and pro-inflammatory cytokine expression induced by CpG DNAs (D- and K-type), CpG-DNAs complexed with DOTAP, and genomic DNAs complexed with LL37. Mechanistically, EGA suppressed phosphorylation of IKKα/ß, STAT1, Akt, and p38, and decreased colocalization of CpG oligodeoxynucleotides with LAMP+ endo-lysosomes. EGA also diminished type 1 IFN expression by pDCs from systemic lupus erythematosus patients. Therefore, our findings help understand mechanisms for the bifurcated cytokine responses by pDCs and support future examination of the potential benefit of EGA in treating type 1 IFN-associated inflammatory diseases in the future.
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Citocinas , Receptor Toll-Like 9 , Humanos , Citocinas/metabolismo , Receptor Toll-Like 9/metabolismo , Interferón-alfa/metabolismo , Células Dendríticas/metabolismo , Endosomas/metabolismoRESUMEN
Nuclear hormone receptors (NHRs) expressed by dendritic cells (DCs), the major immune inducers and regulators, could play important roles in host immunity. Assessment of NHRs expressed by DCs in the vaginal mucosa (VM), in comparison with those expressed by DCs in other tissues, will thus help us understand the immunology of human vagina. This study identified 16 NHR transcripts that are differentially expressed among 8 different antigen-presenting cell (APC) subsets isolated from human VM, skin, and blood. The expression profiles of NHRs were largely tissue specific. VM APCs expressed increased levels of LXRA, RXRA, ESRRA, ESRRAP2, and PPARG, whereas skin and blood APCs expressed increased levels of NURR1, NOR1 and RARA. Of interest, female sex hormone receptors, ESR1 and PGR, were found to be mainly expressed by non-APC cell types in the VM; ESR1 by HLA-DR+CD34+ and PGR by HLA-DR- cells. ERα and PR were expressed by vimentin+ cells in the VM, but not in human skin. ERα, but not PR, was also expressed in CD10+ cells in the lamina propria of VM. In conclusion, NHR expression by APC subsets is tissue- and cell type-specific. Future studies on the roles of individual NHRs expressed by different cell types, including DC subsets, in the human VM are warranted.
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Células Dendríticas , Receptor alfa de Estrógeno , Humanos , Femenino , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Vagina , Antígenos HLA-DR/metabolismo , Membrana MucosaRESUMEN
Female sex hormones affect the immune response in the lower female genital tract. To understand their mechanisms of action, it is essential to define cell types expressing estrogen receptor (ER) and/or progesterone receptor (PR) in the human vaginal mucosa (VM). Here, we report that none of the dendritic cell (DC) subsets in the human VM expressed ERα or PR in situ. However, they were capable of expressing ERα, but not PR, after in vitro culture of the whole VM tissues. Similarly, ERα and/or PR expression by T cells in the VM tissues was also inducible rather than constitutive. In contrast, ERα and/or PR were constitutively expressed in HLA-DR- non-immune cell types (vimentin+, desmin+, or CD10+). These new findings will help us understand the mechanisms of action of female sex hormones in the modulation of immune response in the human VM and lower female genital tract.
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Membrana Mucosa/metabolismo , Receptores de Estrógenos/biosíntesis , Receptores de Progesterona/biosíntesis , Vagina/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Células Dendríticas/metabolismo , Femenino , Humanos , Persona de Mediana Edad , Linfocitos T/metabolismoRESUMEN
The epithelium-associated cytokine thymic stromal lymphopoietin (TSLP) can induce OX40L and CCL17 expression by myeloid dendritic cells (mDCs), which contributes to aberrant Th2-type immune responses. Herein, we report that such TSLP-induced Th2-type immune response can be effectively controlled by Dectin-1, a C-type lectin receptor expressed by mDCs. Dectin-1 stimulation induced STAT3 activation and decreased the transcriptional activity of p50-RelB, both of which resulted in reduced OX40L expression on TSLP-activated mDCs. Dectin-1 stimulation also suppressed TSLP-induced STAT6 activation, resulting in decreased expression of the Th2 chemoattractant CCL17. We further demonstrated that Dectin-1 activation was capable of suppressing ragweed allergen (Amb a 1)-specific Th2-type T cell response in allergy patients ex vivo and house dust mite allergen (Der p 1)-specific IgE response in non-human primates in vivo. Collectively, this study provides a molecular explanation of Dectin-1-mediated suppression of Th2-type inflammatory responses and suggests Dectin-1 as a target for controlling Th2-type inflammation.
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Citocinas/farmacología , Células Dendríticas/inmunología , Hipersensibilidad/inmunología , Inmunidad/efectos de los fármacos , Lectinas Tipo C/metabolismo , Subunidad p50 de NF-kappa B/metabolismo , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT6/metabolismo , Transducción de Señal/efectos de los fármacos , Células Th2/inmunología , Factor de Transcripción ReIB/metabolismo , Adulto , Alérgenos/administración & dosificación , Alérgenos/inmunología , Animales , Antígenos Dermatofagoides/administración & dosificación , Antígenos Dermatofagoides/inmunología , Antígenos de Plantas/farmacología , Estudios de Casos y Controles , Dermatophagoides farinae/inmunología , Modelos Animales de Enfermedad , Femenino , Células HEK293 , Humanos , Hipersensibilidad/sangre , Lectinas Tipo C/agonistas , Macaca mulatta , Masculino , Persona de Mediana Edad , Ligando OX40/metabolismo , Proteínas de Plantas/farmacología , Células Th2/efectos de los fármacos , beta-Glucanos/farmacología , Linfopoyetina del Estroma TímicoRESUMEN
Regulatory B cells (Bregs) contribute to immune regulation. However, the mechanisms of action of Bregs remain elusive. Here, we report that T cell immunoreceptor with Ig and ITIM domains (TIGIT) expressed on human memory B cells especially CD19+CD24hiCD27+CD39hiIgD-IgM+CD1c+ B cells is essential for effective immune regulation. Mechanistically, TIGIT on memory B cells controls immune response by directly acting on T cells and by arresting proinflammatory function of dendritic cells, resulting in the suppression of Th1, Th2, Th17, and CXCR5+ICOS+ T cell response while promoting immune regulatory function of T cells. TIGIT+ memory B cells are also superior to other B cells at expressing additional inhibitory molecules, including IL-10, TGFß1, granzyme B, PD-L1, CD39/CD73, and TIM-1. Lack or decrease of TIGIT+ memory B cells is associated with increased donor-specific antibody and TFH response, and decreased Treg response in renal and liver allograft patients. Therefore, TIGIT+ human memory B cells play critical roles in immune regulation.
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Linfocitos B Reguladores/inmunología , Linfocitos B/inmunología , Receptores Inmunológicos/inmunología , Antígenos CD/metabolismo , Antígenos CD1 , Antígenos CD19 , Apirasa/metabolismo , Antígeno B7-H1 , Antígeno CD24/metabolismo , Glicoproteínas , Humanos , Inmunoglobulina D , Inmunoglobulina M , Proteína Coestimuladora de Linfocitos T Inducibles , Interleucina-10 , Receptores CXCR5 , Receptores Inmunológicos/genética , Células TH1 , Células Th17/inmunología , Células Th2 , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismoAsunto(s)
Antialérgicos/uso terapéutico , Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Pulmón/efectos de los fármacos , Obesidad/complicaciones , Omalizumab/uso terapéutico , Antialérgicos/efectos adversos , Antiasmáticos/efectos adversos , Asma/complicaciones , Asma/inmunología , Asma/fisiopatología , Índice de Masa Corporal , Humanos , Pulmón/inmunología , Pulmón/fisiopatología , Obesidad/inmunología , Obesidad/fisiopatología , Omalizumab/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Anti-IgE (omalizumab) has been used for the treatment of moderate-to-severe asthma that is not controlled by inhaled steroids. Despite its success, it does not always provide patients with significant clinical benefits. OBJECTIVE: To investigate the transcriptional variations between omalizumab responders and non-responders and to study the mechanisms of action of omalizumab. METHODS: The whole blood transcriptomes of moderate-to-severe adult asthma patients (N = 45:34 responders and 11 non-responders) were analysed over the course of omalizumab treatment. Non-asthmatic healthy controls (N = 17) were used as controls. RESULTS: Transcriptome variations between responders and non-responders were identified using the genes significant (FDR < 0.05) in at least one comparison of each patient response status and time point compared with control subjects. Using gene ontology and network analysis, eight clusters of genes were identified. Longitudinal analyses of individual clusters revealed that responders could maintain changes induced with omalizumab treatment and become more similar to the control subjects, while non-responders tend to remain more similar to their pre-treatment baseline. Further analysis of an inflammatory gene cluster revealed that genes associated with neutrophil/eosinophil activities were up-regulated in non-responders and, more importantly, omalizumab did not significantly alter their expression levels. The application of modular analysis supported our findings and further revealed variations between responders and non-responders. CONCLUSION AND CLINICAL RELEVANCE: This study provides not only transcriptional variations between omalizumab responders and non-responders, but also molecular insights for controlling asthma by omalizumab.
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Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Perfilación de la Expresión Génica , Pulmón/efectos de los fármacos , Omalizumab/uso terapéutico , Transcriptoma , Adulto , Anciano , Antiasmáticos/efectos adversos , Asma/sangre , Asma/genética , Asma/fisiopatología , Biomarcadores/sangre , Estudios de Casos y Controles , Análisis por Conglomerados , Femenino , Redes Reguladoras de Genes , Humanos , Estudios Longitudinales , Pulmón/metabolismo , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Omalizumab/efectos adversos , Transducción de Señal/genética , Resultado del Tratamiento , Adulto JovenRESUMEN
Although IL-10-producing regulatory B cells (Bregs) play important roles in immune regulation, their surface phenotypes and functional characteristics have not been fully investigated. In this study, we report that the frequency of IL-10-producing Bregs in human peripheral blood, spleens, and tonsils is similar, but they display heterogenous surface phenotypes. Nonetheless, CD24hiCD38hi transitional B cells (TBs) and CD24hiCD27+ B cells (human equivalent of murine B10 cells) are the major IL-10-producing B cells. They both suppress CD4+ T cell proliferation as well as IFN-γ/IL-17 expression. However, CD24hiCD27+ B cells were more efficient than TBs at suppressing CD4+ T cell proliferation and IFN-γ/IL-17 expression, whereas they both coexpress IL-10 and TNF-α. TGF-ß1 and granzyme B expression were also enriched within CD24hiCD27+ B cells, when compared with TBs. Additionally, CD24hiCD27+ B cells expressed increased levels of surface integrins (CD11a, CD11b, α1, α4, and ß1) and CD39 (an ecto-ATPase), suggesting that the in vivo mechanisms of action of the two Breg subsets are not the same. Lastly, we also report that liver allograft recipients with plasma cell hepatitis had significant decreases of both Breg subsets.
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ADP-Ribosil Ciclasa 1/inmunología , Linfocitos B Reguladores/inmunología , Antígeno CD24/inmunología , Hepatitis Autoinmune/inmunología , Glicoproteínas de Membrana/inmunología , Células Plasmáticas/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología , ADP-Ribosil Ciclasa 1/sangre , Linfocitos B Reguladores/patología , Antígeno CD24/sangre , Hepatitis Autoinmune/sangre , Hepatitis Autoinmune/patología , Humanos , Glicoproteínas de Membrana/sangre , Células Plasmáticas/patología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/sangreRESUMEN
BACKGROUND: Autoimmune demyelinating diseases (ADD) are a major cause of neurological disability due to autoreactive cellular and humoral immune responses against brain antigens. A cure for chronic ADD could be obtained by appropriate immunomodulation. METHODS: We implemented a preclinical scheme to foster immune tolerance to myelin oligodendrocyte glycoprotein (MOG), in a cynomolgus-macaque model of experimental autoimmune encephalomyelitis (EAE), in which administration of recombinant human MOG (rhMOG) elicits brain inflammation mediated by MOG-autoreactive CD4+ lymphocytes and anti-MOG IgG. For immunotherapy, we used a recombinant antibody (Ab) directed against the dendritic cell-asialoglycoprotein receptor (DC-ASGPR) fused either to MOG or a control antigen PSA (prostate-specific antigen). FINDINGS: rhMOG and the anti-DC-ASGPR-MOG were respectively detected in CD1a+ DCs or CD163+ cells in the skin of macaques. Intradermal administration of anti-DC-ASGPR-MOG, but not control anti-DC-ASGPR-PSA, was protective against EAE. The treatment prevented the CD4+ T cell activation and proinflammatory cytokine production observed in controls. Moreover, the administration of anti-DC-ASGPR-MOG induced MOG-specific CD4+CD25+FOXP3+CD39+ regulatory lymphocytes and favoured an upsurge in systemic TGFß and IL-8 upon rhMOG re-administration in vivo. INTERPRETATION: We show that the delivery of an anti-DC-ASGPR-MOG allows antigen-specific adaptive immune modulation to prevent the breach of immune tolerance to MOG. Our findings pave the way for therapeutic vaccines for long-lasting remission to grave encephalomyelitis with identified autoantigens, such as ADD associated with anti-MOG autoantibodies. FUND: Work supported by the French ANR (ANR-11-INBS-0008 and ANR-10-EQPX-02-01), NIH (NIH 1 R01 AI 105066), the Baylor Scott and White Healthcare System funding and Roche Research Collaborative grants.
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Autoanticuerpos/inmunología , Autoantígenos/inmunología , Encefalomielitis Autoinmune Experimental/prevención & control , Glicoproteína Mielina-Oligodendrócito/inmunología , Vacunas/inmunología , Animales , Citocinas/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Encefalomielitis Autoinmune Experimental/diagnóstico , Humanos , Linfocitos/inmunología , Linfocitos/metabolismo , Macaca , Glicoproteína Mielina-Oligodendrócito/antagonistas & inhibidores , Fenotipo , Proteínas Recombinantes , Vacunación , Vacunas/administración & dosificaciónRESUMEN
The types and magnitude of Ag-specific immune responses can be determined by the functional plasticity of dendritic cells (DCs). However, how DCs display functional plasticity and control host immune responses have not been fully understood. In this study, we report that ligation of DC-asialoglycoprotein receptor (DC-ASGPR), a C-type lectin receptor (CLR) expressed on human DCs, resulted in rapid activation of Syk, followed by PLCγ2 and PKCδ engagements. However, different from other Syk-coupled CLRs, including Dectin-1, signaling cascade through DC-ASGPR did not trigger NF-κB activation. Instead, it selectively activated MAPK ERK1/2 and JNK. Rapid and prolonged phosphorylation of ERK1/2 led to sequential activation of p90RSK and CREB, which consequently bound to IL10 promoter and initiated cytokine expression. In addition, DC-ASGPR ligation activated Akt, which differentially regulated the activities of GSK-3α/ß and ß-catenin and further contributed to IL-10 expression. Our observations demonstrate that DC-ASGPR induces IL-10 expression via an intrinsic signaling pathway, which provides a molecular explanation for DC-ASGPR-mediated programing of DCs to control host immune responses.
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Receptor de Asialoglicoproteína/inmunología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/inmunología , Interleucina-10/inmunología , Transducción de Señal/inmunología , Activación Transcripcional/inmunología , Células Cultivadas , Citocinas/inmunología , Células Dendríticas/inmunología , Humanos , Factores Inmunológicos/inmunología , Lectinas Tipo C/inmunología , Sistema de Señalización de MAP Quinasas/inmunología , FN-kappa B/inmunología , Fosforilación/inmunología , Regiones Promotoras Genéticas/inmunologíaRESUMEN
Graft-versus-host disease (GVHD) is one of the major obstacles for the success of allogeneic hematopoietic stem cell transplantation. Here, we report that the interaction between OX40L and OX40 is of critical importance for both induction and progression of acute GVHD (aGVHD) driven by human T cells. Anti-human OX40L monoclonal antibody (hOX40L) treatment could thus effectively reduce the disease severity in a xenogeneic-aGVHD (x-aGVHD) model in both preventative and therapeutic modes. Mechanistically, blocking OX40L-OX40 interaction with an anti-hOX40L antibody reduces infiltration of human T cells in target organs, including liver, gut, lung, and skin. It also decreases IL-21- and TNF-producing T cell responses, while promoting regulatory T cell (Treg) responses without compromising the cytolytic activity of CD8+ T cells. Single blockade of hOX40L was thus more effective than dual blockade of IL-21 and TNF in reducing the severity of aGVHD as well as mortality. Data from this study indicate that OX40L-OX40 interactions play a central role in the pathogenesis of aGVHD induced by human T cells. Therapeutic strategies that can efficiently interrupt OX40L-OX40 interaction in patients might have potential to provide patients with an improved clinical benefit.
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Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/metabolismo , Ligando OX40/metabolismo , Receptores OX40/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Enfermedad Aguda , Animales , Anticuerpos Monoclonales/farmacología , Citocinas/metabolismo , Citotoxicidad Inmunológica/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Progresión de la Enfermedad , Etanercept/farmacología , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/patología , Humanos , Interleucinas/antagonistas & inhibidores , Leucocitos/efectos de los fármacos , Leucocitos/inmunología , Leucocitos/metabolismo , Ratones , Ligando OX40/antagonistas & inhibidores , Unión Proteica , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismoRESUMEN
BACKGROUND: IL-10-producing regulatory B cells (Bregs) are widely ascribed immune regulatory functions. However, Breg subsets in human asthma have not been fully investigated. OBJECTIVE: We studied Breg subsets in adult allergic asthma patients by assessing two major parameters, frequency and IL-10 expression. We then investigated factors that affect these two parameters in patients. METHODS: Peripheral blood mononuclear cells (PBMCs) of adult allergic asthma patients (N = 26) and non-asthmatic controls (N = 28) were used to assess the frequency of five subsets of transitional B cells (TBs), three subsets of CD24high CD27+ B cells and B1 cells. In addition to clinical data, IL-10 expression by individual Breg subsets was assessed by flow cytometry. RESULTS: Asthma patients had decreases of CD5+ and CD1d+ CD5+ , but an increase of CD27+ TBs which was significant in patients with moderate asthma (60 < FEV1 < 80). Regardless of asthma severity, there was no significant alteration in the frequencies of 6 other Breg subsets tested. However, we found that oral corticosteroid (OCS) significantly affected the frequency of Bregs in Breg subset-specific manners. OCS decreased CD5+ and CD1d+ CD5+ TBs, but increased CD27+ TBs and CD10+ CD24high CD27+ cells. Furthermore, OCS decreased IL-10 expression by CD27+ TBs, all 3 CD24high CD27+ B cell subsets (CD5+ , CD10+ and CD1d+ ) and B1 cells. OCS-mediated inhibition of IL-10 expression was not observed in the other Breg subsets tested. CONCLUSION & CLINICAL RELEVANCE: Alterations in the frequency of Bregs and their ability to express IL-10 are Breg subset-specific. OCS treatment significantly affects the frequency as well as their ability to express IL-10 in Breg subset-specific manners.
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Corticoesteroides/administración & dosificación , Asma , Linfocitos B Reguladores , Administración Oral , Adulto , Antígenos CD/sangre , Antígenos CD/inmunología , Asma/sangre , Asma/tratamiento farmacológico , Asma/inmunología , Asma/patología , Linfocitos B Reguladores/inmunología , Linfocitos B Reguladores/metabolismo , Linfocitos B Reguladores/patología , Femenino , Humanos , Interleucina-10/sangre , Interleucina-10/inmunología , Recuento de Linfocitos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: T cells play a central role in chronic inflammation in asthma. However, the roles of individual subsets of T cells in the pathology of asthma in patients remain to be better understood. METHODS: We investigated the potential signatures of T cell subset phenotypes in asthma using fresh whole blood from adult atopic asthma patients (n = 43) and non-asthmatic control subjects (n = 22). We further assessed their potential clinical implications by correlating asthma severity. RESULTS: We report four major features of CD4+ T cells in the blood of atopic asthma patients. First, patients had a profound increase of CCR7+ memory CD4+ T cells, but not CCR7- memory CD4+ T cells. Second, an increase in CCR4+ CD4+ T cells in patients was mainly attributed to the increase of CCR7+ memory CD4+ T cells. Accordingly, the frequency of CCR4+CCR7+ memory CD4+ T cells correlated with asthma severity. Current common asthma therapeutics (including corticosteroids) were not able to affect the frequency of CCR4+CCR7+ memory CD4+ T cell subsets. Third, patients had an increase of Tregs, as assessed by measuring CD25, Foxp3, IL-10 and CTLA-4 expression. However, asthma severity was inversely correlated only with the frequency of CTLA-4+ CD4+ T cells. Lastly, patients and control subjects have similar frequencies of CD4+ T cells that express CCR5, CCR6, CXCR3, CXCR5, CD11a, or α4 integrin. However, the frequency of α4+ CD4+ T cells in patients correlated with asthma severity. CONCLUSIONS: CCR4+CCR7+ memory, but not CCR4+CCR7- memory, α4+, and CTLA4+ CD4+ T cells in patients show significant clinical implications in atopic asthma. Current common therapeutics cannot alter the frequency of such CD4+ T cell subsets in adult atopic asthma patients.
RESUMEN
The lipopolysaccharide (LPS) is a major virulence factor of Brucella, a facultative intracellular pathogenic Gram-negative bacterium. Brucella LPS exhibits a low toxicity and its atypical structure was postulated to delay the host immune response, favouring the establishment of chronic disease. Here we carried out an in-depth in vitro and in vivo characterisation of the immunomodulatory effects of Brucella LPS on different dendritic cell (DC) subpopulations. By using LPSs from bacteria that share some of Brucella LPS structural features, we demonstrated that the core component of B. melitensis wild-type (Bm-wt) LPS accounts for the low activation potential of Brucella LPS in mouse GM-CSF-derived (GM-) DCs. Contrary to the accepted dogma considering Brucella LPS a poor TLR4 agonist and DC activator, Bm-wt LPS selectively induced expression of surface activation markers and cytokine secretion from Flt3-Ligand-derived (FL-) DCs in a TLR4-dependent manner. It also primed in vitro T cell proliferation by FL-DCs. In contrast, modified LPS with a defective core purified from Brucella carrying a mutated wadC gene (Bm-wadC), efficiently potentiated mouse and human DC activation and T cell proliferation in vitro. In vivo, Bm-wt LPS promoted scant activation of splenic DC subsets and limited recruitment of monocyte- DC like cells in the spleen, conversely to Bm-wadC LPS. Bm-wadC live bacteria drove high cytokine secretion levels in sera of infected mice. Altogether, these results illustrate the immunomodulatory properties of Brucella LPS and the enhanced DC activation ability of the wadC mutation with potential for vaccine development targeting Brucella core LPS structure.
Asunto(s)
Brucella melitensis/química , Citocinas/metabolismo , Células Dendríticas/inmunología , Lipopolisacáridos/inmunología , Animales , Proliferación Celular , Células Cultivadas , Células Dendríticas/efectos de los fármacos , Humanos , Lipopolisacáridos/aislamiento & purificación , Ratones , Bazo/inmunología , Linfocitos T/inmunología , Receptor Toll-Like 4/metabolismoRESUMEN
Human papillomavirus (HPV), particularly HPV16 and HPV18, can cause cancers in diverse anatomical sites, including the anogenital and oropharyngeal (throat) regions. Therefore, development of safe and clinically effective therapeutic vaccines is an important goal. Herein, we show that a recombinant fusion protein of a humanized antibody to CD40 fused to HPV16.E6/7 (αCD40-HPV16.E6/7) can evoke HPV16.E6/7-specific CD8+ and CD4+ T-cell responses in head-and-neck cancer patients in vitro and in human CD40 transgenic (hCD40Tg) mice in vivo The combination of αCD40-HPV16.E6/7 and poly(I:C) efficiently primed HPV16.E6/7-specific T cells, particularly CD8+ T cells, in hCD40Tg mice. Inclusion of montanide enhanced HPV16.E6/7-specific CD4+, but not CD8+, T-cell responses. Poly(I:C) plus αCD40-HPV16.E6/7 was sufficient to mount both preventative and therapeutic immunity against TC-1 tumors in hCD40Tg mice, significantly increasing the frequency of HPV16-specific CD8+ CTLs in the tumors, but not in peripheral blood. In line with this, tumor volume inversely correlated with the frequency of HPV16.E6/7-specific CD8+ T cells in tumors, but not in blood. These data suggest that CD40-targeting vaccines for HPV-associated malignancies can provide a highly immunogenic platform with a strong likelihood of clinical benefit. Data from this study offer strong support for the development of CD40-targeting vaccines for other cancers in the future. Cancer Immunol Res; 4(10); 823-34. ©2016 AACR.
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Antígenos CD40/inmunología , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/inmunología , Neoplasias de Cabeza y Cuello/inmunología , Vacunas contra Papillomavirus/inmunología , Animales , Antivirales/inmunología , Linfocitos T CD4-Positivos/inmunología , Femenino , Papillomavirus Humano 16/inmunología , Humanos , Inmunidad Celular , Ratones Endogámicos C57BL , Ratones Transgénicos , Poli I-C/inmunología , Proteínas Recombinantes de Fusión/inmunología , Células Tumorales Cultivadas , Neoplasias del Cuello Uterino/prevención & control , Neoplasias del Cuello Uterino/virología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Fifteen new substituted adenines were synthesized as potential TLR7 agonists. These compounds, along with 9 previously reported compounds, were analyzed for TLR7 activity and for the selective stimulation of B cell proliferation. Several functionalized derivatives exhibit significant activity, suggesting their potential for use as vaccine adjuvants.
Asunto(s)
Adenina/análogos & derivados , Adyuvantes Inmunológicos/síntesis química , Receptor Toll-Like 7/agonistas , Adenina/síntesis química , Adenina/farmacología , Adyuvantes Inmunológicos/química , Adyuvantes Inmunológicos/farmacología , Amidas/síntesis química , Amidas/química , Amidas/farmacología , Linfocitos B/citología , Linfocitos B/efectos de los fármacos , Linfocitos B/metabolismo , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Cristalografía por Rayos X , Humanos , Activación de Linfocitos/efectos de los fármacos , Conformación Molecular , Receptor Toll-Like 7/metabolismoRESUMEN
Dendritic cells (DCs) are major antigen-presenting cells that can efficiently prime and cross-prime antigen-specific T cells. Delivering antigen to DCs via surface receptors is thus an appealing strategy to evoke cellular immunity. Nonetheless, which DC surface receptor to target to yield the optimal CD8(+) and CD4(+) T cell responses remains elusive. Herein, we report the superiority of CD40 over 9 different lectins and scavenger receptors at evoking antigen-specific CD8(+) T cell responses. However, lectins (e.g., LOX-1 and Dectin-1) were more efficient than CD40 at eliciting CD4(+) T cell responses. Common and distinct patterns of subcellular and intracellular localization of receptor-bound αCD40, αLOX-1 and αDectin-1 further support their functional specialization at enhancing antigen presentation to either CD8(+) or CD4(+) T cells. Lastly, we demonstrate that antigen targeting to CD40 can evoke potent antigen-specific CD8(+) T cell responses in human CD40 transgenic mice. This study provides fundamental information for the rational design of vaccines against cancers and viral infections.