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1. Elevated cyclic AMP inhibits mycobacterium tuberculosis-stimulated T-cell IFN-γ secretion through type I protein kinase A

Author

Yoon-tae Chung, Javier Oscar Jurado, Virginia Pasquinelli, Buka Samten, Xisheng Wang, Peter F. Barnes, Na Yi, and Verónica E. García

Subjects
0301 basic medicine, T-Lymphocytes, T cell, Activating transcription factor, CREB, TUBERCULOSIS, Peripheral blood mononuclear cell, Mycobacterium tuberculosis, Ciencias Biológicas, Major Articles and Brief Reports, Interferon-gamma, 03 medical and health sciences, chemistry.chemical_compound, Biología Celular, Microbiología, Latent Tuberculosis, Cyclic AMP, medicine, Humans, Immunology and Allergy, Cyclic adenosine monophosphate, CYCLIC ADENOSINE MONOPHOSPHATE, TRANSCRIPTION FACTOR, Promoter Regions, Genetic, Protein kinase A, Antigens, Bacterial, Activating Transcription Factor 2, Latent tuberculosis, biology, HUMAN, medicine.disease, biology.organism_classification, Molecular biology, Interleukin-10, CYTOKINE, Cyclic AMP-Dependent Protein Kinase Type I, 030104 developmental biology, Infectious Diseases, medicine.anatomical_structure, chemistry, Leukocytes, Mononuclear, biology.protein, CIENCIAS NATURALES Y EXACTAS, Protein Binding, Signal Transduction
Abstract

Cyclic adenosine monophosphate (cAMP) is critical in immune regulation, and its role in tuberculosis infection remains unclear. We determined the levels of cAMP in peripheral blood mononuclear cells (PBMC) from tuberculosis patients and the mechanisms for cAMP suppression of IFN-γ production. PBMC from tuberculosis patients contained significantly elevated cAMP than latent tuberculosis infected subjects (LTBI), with an inverse correlation with IFN-γ production. Consistent with this, the expression of cAMP response element binding protein (CREB), activating transcription factor (ATF)-2 and c-Jun were reduced in tuberculosis patients compared with LTBI. PKA type I specific cAMP analogs inhibited Mtb-stimulated IFN-g production by PBMC through suppression of Mtb-induced IFN-γ promoter binding activities of CREB, ATF-2, and c-Jun and also miR155, the target miRNA of these transcription factors. Neutralizing both IL-10 and TGF-β1 or supplementation of IL-12 restored cAMP-suppressed IFN-g production. We conclude that increased cAMP inhibits IFN-g production through PKA type I pathway in tuberculosis infection. Fil: Yoon-tae Chung. University of California at Los Angeles. School of Medicine; Estados Unidos Fil: Pasquineli, V. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: J. Jurado. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Xisheng Wang. University of California at Los Angeles. School of Medicine; Estados Unidos Fil: Na Yi. University of California at Los Angeles. School of Medicine; Estados Unidos Fil: Peter Barnes. University of California at Los Angeles. School of Medicine; Estados Unidos Fil: García, Verónica Edith. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Buka Samten. University of California at Los Angeles. School of Medicine; Estados Unidos

Published
2018

2. Role Played by the Programmed Death‐1–Programmed Death Ligand Pathway during Innate Immunity againstMycobacterium tuberculosis

Author

Ivana Belén Alvarez, Eduardo Abbate, Virginia Pasquinelli, Rosa M. Musella, Verónica E. García, Javier Oscar Jurado, and Silvia de la Barrera

Subjects
Adult, Programmed Cell Death 1 Ligand 2 Protein, Otras Ciencias Biológicas, Programmed Cell Death 1 Receptor, Apoptosis, Biology, B7-H1 Antigen, purl.org/becyt/ford/1 [https], Ciencias Biológicas, Mycobacterium tuberculosis, Interferon-gamma, Antigens, CD, Humans, Tuberculosis, Immunology and Allergy, purl.org/becyt/ford/1.6 [https], Innate immune system, Human leukocyte interferon, Gene Expression Profiling, biology.organism_classification, Virology, Immunity, Innate, Innate Immunity, Up-Regulation, Killer Cells, Natural, Blood, Costimulation, Infectious Diseases, Nk Cells, Pleural fluid, Intercellular Signaling Peptides and Proteins, Pleura, Programmed death 1, Apoptosis Regulatory Proteins, CIENCIAS NATURALES Y EXACTAS, Programmed death
Abstract

Tuberculous pleurisy allows the study of specific cells at the site of Mycobacterium tuberculosis infection. Among pleural lymphocytes, natural killer (NK) cells are a major source of interferon γ (IFN-γ), and their functions are regulated by activating and inhibitory receptors. Programmed death-1 (PD-1), programmed death ligand 1 (PD-L1), and programmed death ligand 2 (PD-L2) are recognized inhibitory receptors in adaptive immunity, but their role during innate immunity remains poorly understood. We investigated the PD-1:PDL1/ PD-L2 pathway on NK cell effector functions in peripheral blood and pleural fluid from patients with tuberculosis. M. tuberculosis stimulation significantly up-regulated PD-1, PD-L1, and PD-L2 levels on NK cells. Interestingly, a direct correlation between PD-1 and IFN-γ expression on NK cells was observed. Moreover, blockade of the PD-1 pathway markedly augmented lytic degranulation and IFN-γ production of NK cells against M. tuberculosis. Furthermore, PD-1+ NK cells displayed a diminished IFN-γ mean fluorescence intensity, denoting the relevance of PD-1 on IFN-γ regulation. Together, we described a novel inhibitory role played by PD-1:PD-L interactions in innate immunity in tuberculosis. © 2010 by the Infectious Diseases Society of America. Fil: Alvarez, Ivana Belén. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Pasquinelli, Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Jurado, Javier Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Abbate, Pablo Eduardo. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; Argentina Fil: Musella, Rosa María. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; Argentina Fil: de la Barrera, Silvia Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex". Departamento de Inmunología y Medicina Experimental; Argentina Fil: García, Verónica Edith. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina

Published
2010

3. IFN-γ Production during Active Tuberculosis Is Regulated by Mechanisms That Involve IL-17, SLAM, and CREB

Author

María Florencia Quiroga, Peter F. Barnes, Virginia Pasquinelli, Ivana Belén Alvarez, Buka Samten, James C. Townsend, Javier Oscar Jurado, and Verónica E. García

Subjects
Otras Ciencias Biológicas, Receptors, Cell Surface, TUBERCULOSIS, CREB, Article, Ciencias Biológicas, purl.org/becyt/ford/1 [https], Interferon-gamma, Signaling Lymphocytic Activation Molecule Family Member 1, Antigens, CD, Signaling proteins, Humans, Tuberculosis, Immunology and Allergy, Phosphorylation, Cyclic AMP Response Element-Binding Protein, purl.org/becyt/ford/1.6 [https], IFN-GAMMA, biology, Human leukocyte interferon, Interleukin-17, Gene Expression Regulation, Bacterial, Active tuberculosis, Virology, Infectious Diseases, SIGNALING PROTEINS, Lymphocyte activation, biology.protein, Interleukin 17, CIENCIAS NATURALES Y EXACTAS, Ifn gamma
Abstract

Interferon-γ (IFN-γ) is crucial for protection against Mycobacterium tuberculosis, and the transcription factor cAMP response element binding protein (CREB) increases IFN-γ transcription. We determined whether the transmembrane receptor signaling lymphocyte activation molecule (SLAM) and interleukin-17 (IL-17) affect CREB phosphorylation and IFN-γ production in persons with tuberculosis. When T cells from patients with tuberculosis were activated with M. tuberculosis, 80% of SLAM+ T cells expressed phosphorylated CREB, and SLAM activation increased CREB phosphorylation and IFN-γ production. In contrast, IL-17 down-regulated SLAM expression, CREB phosphorylation, and IFN-γ production. Therefore, IL-17 and SLAM have opposing effects on IFN-γ production through CREB activation in persons with tuberculosis. © 2009 by the Infectious Diseases Society of America. All rights reserved. Fil: Pasquinelli, Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Townsend, James C.. University of Texas; Estados Unidos Fil: Jurado, Javier Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Alvarez, Ivana Belén. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Quiroga, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Barnes, Peter F.. University of Texas; Estados Unidos Fil: Samten, Buka. University of Texas; Estados Unidos Fil: García, Verónica Edith. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina

Published
2009

4. Programmed Death (PD)-1:PD-Ligand 1/PD-Ligand 2 Pathway Inhibits T Cell Effector Functions during Human Tuberculosis

Author

María Florencia Quiroga, Virginia Pasquinelli, Javier Oscar Jurado, Eduardo Abbate, Rosa M. Musella, H. Eduardo Chuluyan, Gustavo J. Martinez, Ivana Belén Alvarez, and Verónica E. García

Subjects
CIENCIAS MÉDICAS Y DE LA SALUD, Programmed Cell Death 1 Ligand 2 Protein, T-Lymphocytes, CD3, T cell, Programmed Cell Death 1 Receptor, Immunology, Inmunología, Receptors, Cell Surface, CITOQUINAS, Biology, Lymphocyte Activation, TUBERCULOSIS, B7-H1 Antigen, Mycobacterium tuberculosis, Interferon-gamma, Immune system, Signaling lymphocytic activation molecule, Signaling Lymphocytic Activation Molecule Family Member 1, Antigens, CD, medicine, Humans, Tuberculosis, Immunology and Allergy, Antigens, Cells, Cultured, biology.organism_classification, Cell biology, PD1, Medicina Básica, medicine.anatomical_structure, biology.protein, Intercellular Signaling Peptides and Proteins, Apoptosis Regulatory Proteins, CD8, Protein Binding, Signal Transduction
Abstract

Protective immunity against Mycobacterium tuberculosis requires the generation of cell-mediated immunity. We investigated the expression and role of programmed death 1 (PD-1) and its ligands, molecules known to modulate T cell activation, in the regulation of IFN-γ production and lytic degranulation during human tuberculosis. We demonstrated that specific Ag-stimulation increased CD3+PD-1+ lymphocytes in peripheral blood and pleural fluid from tuberculosis patients in direct correlation with IFN-γ production from these individuals. Moreover, M. tuberculosis-induced IFN-γ participated in the up-regulation of PD-1 expression. Blockage of PD-1 or PD-1 and its ligands (PD-Ls: PD-L1, PD-L2) enhanced the specific degranulation of CD8+ T cells and the percentage, of specific IFN-γ-producing lymphocytes against the pathogen, demonstrating that the PD-1:PD-Ls pathway inhibits T cell effector functions during active M. tuberculosis infection. Furthermore, the simultaneous blockage of the inhibitory receptor PD-1 together with the activation of the costimulatory protein signaling lymphocytic activation molecule led to the promotion of protective IFN-γ responses to M. tuberculosis, even in patients with weak cell-mediated immunity against the bacteria. Together, we demonstrated that PD-1 interferes with T cell effector functions against M. tuberculosis, suggesting that PD-1 has a key regulatory role during the immune response of the host to the pathogen. Fil: Jurado, Javier Oscar. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina Fil: Alvarez, Ivana Belén. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Pasquinelli, Virginia. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina Fil: Martínez, Gustavo J.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina Fil: Quiroga, María F.. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina Fil: Abbate, Eduardo. Gobierno de la Ciudad de Buenos Airs. Hospital de Infecciosas "F. Muñiz"; Argentina Fil: Musella, Rosa María. Gobierno de la Ciudad de Buenos Airs. Hospital de Infecciosas "F. Muñiz"; Argentina Fil: Chuluyan, Hector Eduardo. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: García, Verónica Edith. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina

Published
2008

5. Cross‐Talk between CD31 and the Signaling Lymphocytic Activation Molecule–Associated Protein during Interferon‐γ Production againstMycobacterium tuberculosis

Author

Virginia Pasquinelli, María Florencia Quiroga, Peter A. Sieling, Eduardo Abbate, Maria M.E. de Bracco, Rosa M. Musella, Verónica Editha Garcí, Alejandro Malbrán, Eduardo Chuluyan, Andrew C. Issekutz, Gustavo J. Martinez, and Javier Oscar Jurado

Subjects
Tuberculosis, T-Lymphocytes, CD3, medicine.medical_treatment, Biology, Mycobacterium tuberculosis, Interferon-gamma, Signaling lymphocytic activation molecule, Interferon, medicine, Humans, Immunology and Allergy, Interferon gamma, Signaling Lymphocytic Activation Molecule Associated Protein, Tuberculosis, Pulmonary, T-cell receptor, Intracellular Signaling Peptides and Proteins, medicine.disease, biology.organism_classification, Platelet Endothelial Cell Adhesion Molecule-1, Infectious Diseases, Cytokine, Gene Expression Regulation, Immunology, cardiovascular system, biology.protein, Signal Transduction, medicine.drug
Abstract

Effective host defense against tuberculosis requires Th1 cytokine responses. We studied the regulation of interferon (IFN)- gamma production during tuberculosis by investigating the role of CD31, a receptor that attenuates T cell receptor signals. After antigen stimulation, CD3(+)CD31(+) blood lymphocytes decreased in healthy donors and in tuberculosis patients with robust Th1 responses to Mycobacterium tuberculosis and IFN- gamma was secreted only by CD31(-) T cells. In contrast, in patients with weak Th1 cytokine responses to M. tuberculosis, the level of CD3(+)CD31(+) lymphocytes was increased and IFN- gamma production was low. Furthermore, the inverse relationship between CD31 expression and IFN- gamma production was in contrast to signaling lymphocytic activation molecule (SLAM) expression, an IFN- gamma inducer in tuberculosis. Interestingly, CD31 bound to SLAM-associated protein (SAP), an IFN- gamma inhibitor in tuberculosis, and when CD31 and SAP were coexpressed in lymphocytes, their association inhibited the IFN- gamma response to M. tuberculosis. Thus, CD31, when binding to SAP, interferes with Th1 responses, suggesting that CD31 has a key regulatory role in the signaling pathway(s) leading to the IFN- gamma response to M. tuberculosis.

Published
2007

6. Inducible Costimulator: A Modulator of IFN-γ Production in Human Tuberculosis

Author

Javier Oscar Jurado, Virginia Pasquinelli, Peter A. Sieling, María Florencia Quiroga, Rosa M. Musella, Eduardo José Abbate, Liliana Castro Zorrilla, Verónica E. García, and Gustavo J. Martinez

Subjects
Antigens, Differentiation, T-Lymphocyte, Intracellular Fluid, CD3, medicine.medical_treatment, T cell, Immunology, Context (language use), TUBERCULOSIS, Ligands, Cell Line, Ciencias Biológicas, Inducible T-Cell Co-Stimulator Protein, COSTIMULATION, Interferon-gamma, Biología Celular, Microbiología, Antigen, medicine, Humans, Immunology and Allergy, Secretion, Receptor, Tuberculosis, Pulmonary, Cells, Cultured, biology, Antibodies, Monoclonal, T-Lymphocytes, Helper-Inducer, Th1 Cells, Cytokine, medicine.anatomical_structure, ICOS, Gene Expression Regulation, biology.protein, CIENCIAS NATURALES Y EXACTAS
Abstract

Effective host defense against Mycobacterium tuberculosis requires the induction of Th1 cytokine responses. We investigated the regulated expression and functional role of the inducible costimulator (ICOS), a receptor known to regulate Th cytokine production, in the context of human tuberculosis. Patients with active disease, classified as high responder (HR) or low responder (LR) patients according to their in vitro T cell responses against the Ag, were evaluated for T cell expression of ICOS after M.tuberculosis-stimulation. We found that ICOS expression significantly correlated with IFN-g production by tuberculosis patients. ICOS expression levels were regulated in HR patients by Th cytokines: Th1 cytokines increased ICOS levels, whereas Th2-polarizing conditions down-regulated ICOS in these individuals. Besides, in human polarized Th cells, engagement of ICOS increased M. tuberculosis IFN-g production with a magnitude proportional to ICOS levels on those cells. Moreover, ICOS ligation augmented Ag-specific secretion of the Th1 cytokine IFN- from responsive individuals. In contrast, neither Th1 nor Th2 cytokines dramatically affected ICOS levels on Ag-stimulated T cells from LR patients, and ICOS activation did not enhance IFN-g production. However, simultaneous activation of ICOS and CD3 slightly augmented IFN-g secretion by LR patients. Together, our data suggest that the regulation of ICOS expression depends primarily on the response of T cells from tuberculosis patients to the specific Ag. IFN-g released by M. tuberculosis-specific T cells modulates ICOS levels, and accordingly, ICOS ligation induces IFN-g secretion. Thus, ICOS activation may promote the induction of protective Th1 cytokine responses to intracellular bacterial pathogens. Fil: Quiroga, María Florencia. Universidad Abierta Interamericana. Facultad de Medicina. Cátedra de Microbiología Parasitología E Inmunología; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Pasquinelli, Virginia. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Universidad Abierta Interamericana. Facultad de Medicina. Cátedra de Microbiología Parasitología E Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Martínez, Gustavo J.. Universidad Abierta Interamericana. Facultad de Medicina. Cátedra de Microbiología Parasitología E Inmunología; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina Fil: Jurado, Javier Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Universidad Abierta Interamericana. Facultad de Medicina. Cátedra de Microbiología Parasitología E Inmunología; Argentina Fil: Zorrilla, Liliana Castro. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Microbiología. Cátedra de Microbiología, Parasitología e Inmunología; Argentina Fil: Musella, Rosa María. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; Argentina Fil: Abbate, Eduardo José. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; Argentina Fil: Sieling, Peter A.. University of California; Estados Unidos Fil: García, Verónica Edith. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Inmunogenética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Abierta Interamericana. Facultad de Medicina. Cátedra de Microbiología Parasitología E Inmunología; Argentina

Published
2006

7. Phosphorylation of Mitogen-Activated Protein Kinases Contributes to Interferon γ Production in Response to Mycobacterium tuberculosis

Author

Virginia Pasquinelli, Javier Oscar Jurado, Rosa M. Musella, Verónica E. García, Domingo Palmero, Ana Inés Rovetta, Ivana Belén Alvarez, Buka Samten, Peter F. Barnes, and Alejandro Malbrán

Subjects
MAPK/ERK pathway, p38 mitogen-activated protein kinases, T-Lymphocytes, Receptors, Cell Surface, TUBERCULOSIS, p38 Mitogen-Activated Protein Kinases, Mycobacterium tuberculosis, Ciencias Biológicas, purl.org/becyt/ford/1 [https], Interferon-gamma, Major Articles and Brief Reports, Antigen, Signaling Lymphocytic Activation Molecule Family Member 1, Antigens, CD, medicine, Immunology and Allergy, Humans, Interferon gamma, Phosphorylation, Extracellular Signal-Regulated MAP Kinases, purl.org/becyt/ford/1.6 [https], Tuberculosis, Pulmonary, IFN-GAMMA, biology, Kinase, CREB, Bioquímica y Biología Molecular, biology.organism_classification, Enzyme Activation, Infectious Diseases, Immunology, Cancer research, Signal transduction, CIENCIAS NATURALES Y EXACTAS, medicine.drug, Signal Transduction
Abstract

Immune control of Mycobacterium tuberculosis depends on interferon γ (IFN-γ)–producing CD4+ lymphocytes. Previous studies have shown that T cells from patients with tuberculosis produce less IFN-γ, compared with healthy donors, in response to mycobacterial antigens, although IFN-γ responses to mitogens are preserved. In this work, we found that M. tuberculosis–induced IFN-γ production by human T cells correlated with phosphorylation of the mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK), and p38. Moreover, the majority of IFN-γ–producing T cells expressed signaling lymphocyte activation molecule (SLAM), and SLAM activation further increased ERK phosphorylation. Interestingly, patients with tuberculosis had delayed activation of ERK and p38, and this was most marked in patients with the poorest IFN-γ responses (ie, low responders). Besides, SLAM signaling failed to phosphorylate ERK in low responders. Our findings suggest that activation of p38 and ERK, in part through SLAM, mediates T-cell IFN-γ production in response to M. tuberculosis, a pathway that is defective in patients with tuberculosis. Fil: Pasquinelli, Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Rovetta, Ana Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Alvarez, Ivana Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Jurado, Javier Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Musella, Rosa María. Ciudad Autónoma de Buenos Aires. Hospital F. J. Muñiz; Argentina Fil: Palmero, Domingo J.. Ciudad Autónoma de Buenos Aires. Hospital F. J. Muñiz; Argentina Fil: Malbrán, Alejandro. Hospital Británico de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Samten, Buka. University of Texas; Estados Unidos Fil: Barnes, Peter F.. University of Texas; Estados Unidos Fil: García, Verónica Edith. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina

Published
2012

8. IL-17 and IFN-γ expression in lymphocytes from patients with active tuberculosis correlates with the severity of the disease

Author

Nancy Liliana Tateosian, H. Eduardo Chuluyan, Ivana Belén Alvarez, Virginia Pasquinelli, Rosa M. Musella, Ana I. Rovetta, Horacio Eduardo Romeo, Domingo Palmero, Delfina Peña, Javier Oscar Jurado, and Verónica E. García

Subjects
Adult, Male, Tuberculosis, T cell, Immunology, macromolecular substances, TUBERCULOSIS, Severity of Illness Index, CITOCINAS, Mycobacterium tuberculosis, Interferon-gamma, Immune system, Antigen, medicine, Immunology and Allergy, Humans, Interferon gamma, Pathogen, LINFOCITOS, biology, business.industry, Interleukin-17, Cell Biology, Th1 Cells, biology.organism_classification, medicine.disease, Host Defense & Pathophysiology, ENFERMEDADES INFECCIOSAS, medicine.anatomical_structure, Gene Expression Regulation, Th17 Cells, Female, Interleukin 17, business, CELULAS T, medicine.drug
Abstract

Fil: Jurado, Javier O. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Pasquinelli, Virginia. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Álvarez, Ivana B. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Peña, Delfina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Rovetta, Ana I. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Tateosian, Nancy L. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina Fil: Romeo, Horacio. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Musella, Rosa M. Hospital de Infecciosas Francisco Javier Muñiz. División de Tisioneumonología; Argentina Fil: Palmero, Domingo. Hospital de Infecciosas Francisco Javier Muñiz. División de Tisioneumonología; Argentina Fil: Chuluyán, H. Eduardo. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina Fil: García Verónica E. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Abstract: Th1 lymphocytes are crucial in the immune response against Mycobacterium tuberculosis. Nevertheless, IFN-γ alone is not sufficient in the complete eradication of the bacteria, suggesting that other cytokines might be required for pathogen removal. Th17 cells have been associated with M. tuberculosis infection, but the role of IL-17-producing cells in human TB remains to be understood. Therefore, we investigated the induction and regulation of IFN-γ and IL-17 during the active disease. TB patients were classified as High and Low Responder individuals according to their T cell responses against the antigen, and cytokine expression upon M. tuberculosis stimulation was investigated in peripheral blood and pleural fluid. Afterwards, the potential correlation among the proportions of cytokine-producing cells and clinical parameters was analyzed. In TB patients, M. tuberculosis induced IFN-γ and IL-17, but in comparison with BCG-vaccinated healthy donors, IFN-γ results were reduced significantly, and IL-17 was markedly augmented. Moreover, the main source of IL-17 was represented by CD4(+)IFN-γ(+)IL-17(+) lymphocytes, a Th1/Th17 subset regulated by IFN-γ. Interestingly, the ratio of antigen-expanded CD4(+)IFN-γ(+)IL-17(+) lymphocytes, in peripheral blood and pleural fluid from TB patients, was correlated directly with clinical parameters associated with disease severity. Indeed, the highest proportion of CD4(+)IFN-γ(+)IL-17(+) cells was detected in Low Responder TB patients, individuals displaying severe pulmonary lesions, and longest length of disease evolution. Taken together, the present findings suggest that analysis of the expansion of CD4(+)IFN-γ(+)IL-17(+) T lymphocytes in peripheral blood of TB patients might be used as an indicator of the clinical outcome in active TB.

Published
2012

9. CD137 differentially regulates innate and adaptive immunity against Mycobacterium tuberculosis

Author

Javier Oscar Jurado, Romina Haydeé Aspera, Virginia Pasquinelli, Rosa M. Musella, Ivana Belén Alvarez, Dario Fernandez Do Porto, and Verónica E. García

Subjects
CIENCIAS MÉDICAS Y DE LA SALUD, T-Lymphocytes, Immunology, T cells, Inmunología, NK cells, Biology, Adaptive Immunity, TUBERCULOSIS, Mycobacterium tuberculosis, Tumor Necrosis Factor Receptor Superfamily, Member 9, Immune system, Antigen, CD137, Immunology and Allergy, Humans, IL-2 receptor, Antigen-presenting cell, Cells, Cultured, Innate immune system, CYTOKINES, Cell Biology, purl.org/becyt/ford/3.1 [https], Acquired immune system, biology.organism_classification, cytokines, Immunity, Innate, Killer Cells, Natural, Medicina Básica, 4-1BB Ligand, tuberculosis, MONOCYTES, T CELLS, purl.org/becyt/ford/3 [https], Original Article, monocytes, NK CELLS
Abstract

Protective immunity against Mycobacterium tuberculosis is primarily mediated by the interaction of antigen-specific T cells and antigen presenting cells, which often depends on the interplay of cytokines produced by these cells. Costimulatory signals represent a complex network of receptor-ligand interactions that qualitatively and quantitatively influence immune responses. Thus, here we investigated the function of CD137 and CD137L, molecules known to have a central role in immune regulation, during human tuberculosis (TB). We demonstrated that M. tuberculosis antigen stimulation increased both CD137 and CD137L expression on monocytes and NK cells from TB patients and healthy donors, but only up-regulated CD137 on T lymphocytes. Blockage of the CD137 pathway enhanced the levels of interferon (IFN)-γ and tumor necrosis factor (TNF)-α produced by monocytes and NK against M. tuberculosis. In contrast, CD137 blockage significantly decreased the specific degranulation of CD8 + T cells and the percentage of specific IFN-γ and TNF-α producing lymphocytes against the pathogen. Furthermore, inhibition of the CD137 pathway markedly increased T-cell apoptosis. Taken together, our results demonstrate that CD137:CD137L interactions regulate the innate and adaptive immune response of the host against M. tuberculosis. © 2012 Australasian Society for Immunology Inc. All rights reserved. Fil: Fernández Do Porto, Darío Augusto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Jurado, Javier Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Pasquinelli, Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Alvarez, Ivana Belén. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Aspera, Romina Haydeé. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Musella, Rosa María. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; Argentina Fil: García, Verónica Edith. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina

Published
2012

10. Elevated cyclic AMP Acts through PKA type I to Inhibit Mycobacterium tuberculosis ‐induced IFN‐γ Secretion by T cells

Author

Verónica E. García, Xisheng Wang, Virginia Pasquinelli, Javier Oscar Jurado, Peter F. Barnes, Buka Samten, Yoon-tae Chung, James C. Townsend, and Stephen E. Weis

Subjects
Mycobacterium tuberculosis, IFN-gamma secretion, biology, Chemistry, Genetics, biology.organism_classification, Molecular Biology, Biochemistry, Molecular biology, Biotechnology
Published
2008

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