35 results on '"Kalergis, Alexis M."'
Search Results
2. LAG-3 Contribution to T Cell Downmodulation during Acute Respiratory Viral Infections.
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Rodríguez-Guilarte, Linmar, Ramírez, Mario A., Andrade, Catalina A., and Kalergis, Alexis M.
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T cells ,VIRUS diseases ,RESPIRATORY infections ,PROTEIN expression ,VACCINE effectiveness ,MEMBRANE proteins ,T cell receptors - Abstract
LAG-3 is a type I transmembrane protein expressed on immune cells, such as activated T cells, and binds to MHC class II with high affinity. LAG-3 is an inhibitory receptor, and its multiple biological activities on T cell activation and effector functions play a regulatory role in the immune response. Immunotherapies directed at immune checkpoints, including LAG-3, have become a promising strategy for controlling malignant tumors and chronic viral diseases. Several studies have suggested an association between the expression of LAG-3 with an inadequate immune response during respiratory viral infections and the susceptibility to reinfections, which might be a consequence of the inhibition of T cell effector functions. However, important information relative to therapeutic potential during acute viral lower respiratory tract infections and the mechanism of action of the LAG-3 checkpoint remains to be characterized. In this article, we discuss the contribution of LAG-3 to the impairment of T cells during viral respiratory infections. Understanding the host immune response to respiratory infections is crucial for developing effective vaccines and therapies. [ABSTRACT FROM AUTHOR]
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- 2023
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3. Immune Complex-Induced Enhancement of Bacterial Antigen Presentation Requires Fcγ Receptor III Expression on Dendritic Cells
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Herrada, Andrés A., Contreras, Francisco J., Tobar, Jaime A., Pacheco, Rodrigo, and Kalergis, Alexis M.
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- 2007
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4. Female offspring gestated in hypothyroxinemia and infected with human Metapneumovirus (hMPV) suffer a more severe infection and have a higher number of activated CD8+ T lymphocytes.
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Funes, Samanta C., Ríos, Mariana, Fernández-Fierro, Ayleen, Rivera-Pérez, Daniela, Soto, Jorge A., Valbuena, José R., Altamirano-Lagos, María J., Gómez-Santander, Felipe, Jara, Evelyn L., Zoroquiain, Pablo, Roa, Juan C., Kalergis, Alexis M., and Riedel, Claudia A.
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HUMAN metapneumovirus infection ,T cells ,HYPOTHYROIDISM ,VIRAL load ,FETAL development ,FEMALES - Abstract
Maternal thyroid hormones (THs) are essential for the appropriate development of the fetus and especially for the brain. Recently, somestudies have shownthat THs deficiency can also alter the immunesystemdevelopment of the progeny and their ability to mount an appropriate response against infectious agents. In this study, we evaluated whether adult mice gestated under hypothyroxinemia (Hpx) showed an altered immune response against infection with human metapneumovirus (hMPV). We observed that female mice gestated under Hpx showed higher clinical scores after seven days of hMPV infection. Besides, males gestated under Hpx have higher lung viral loads at day seven post-infection. Furthermore, the female offspring gestated in Hpx have already reduced the viral load at day seven and accordingly showed an increasedproportion of activated (CD71
+ and FasL+ ) CD8+ T cells in the lungs, which correlatedwith a trend for a higher histopathological clinical score. These results support that T4 deficiency during gestation might condition the offspring differently in males and females, enhancing their ability to respond to hMPV. [ABSTRACT FROM AUTHOR]- Published
- 2022
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5. Interplay between Lipid Metabolism, Lipid Droplets, and DNA Virus Infections.
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Farías, Mónica A., Diethelm-Varela, Benjamín, Navarro, Areli J., Kalergis, Alexis M., and González, Pablo A.
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DNA virus diseases ,LIPID metabolism ,VIRUS diseases ,DRUG target ,T cells ,DNA viruses - Abstract
Lipid droplets (LDs) are cellular organelles rich in neutral lipids such as triglycerides and cholesterol esters that are coated by a phospholipid monolayer and associated proteins. LDs are known to play important roles in the storage and availability of lipids in the cell and to serve as a source of energy reserve for the cell. However, these structures have also been related to oxidative stress, reticular stress responses, and reduced antigen presentation to T cells. Importantly, LDs are also known to modulate viral infection by participating in virus replication and assembly. Here, we review and discuss the interplay between neutral lipid metabolism and LDs in the replication cycle of different DNA viruses, identifying potentially new molecular targets for the treatment of viral infections. [ABSTRACT FROM AUTHOR]
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- 2022
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6. Pharmacological Inhibition of IRE-1 Alpha Activity in Herpes Simplex Virus Type 1 and Type 2-Infected Dendritic Cells Enhances T Cell Activation.
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Tognarelli, Eduardo I., Retamal-Díaz, Angello, Farías, Mónica A., Duarte, Luisa F., Palomino, Tomás F., Ibañez, Francisco J., Riedel, Claudia A., Kalergis, Alexis M., Bueno, Susan M., and González, Pablo A.
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HUMAN herpesvirus 1 ,ALPHA rhythm ,DENDRITIC cells ,T cells ,UNFOLDED protein response - Abstract
Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections are life-long and highly prevalent in the human population. These viruses persist in the host, eliciting either symptomatic or asymptomatic infections that may occur sporadically or in a recurrent manner through viral reactivations. Clinical manifestations due to symptomatic infection may be mild such as orofacial lesions, but may also translate into more severe diseases, such as ocular infections that may lead to blindness and life-threatening encephalitis. A key feature of herpes simplex viruses (HSVs) is that they have evolved molecular determinants that hamper numerous components of the host's antiviral innate and adaptive immune system. Importantly, HSVs infect and negatively modulate the function of dendritic cells (DCs), by inhibiting their T cell-activating capacity and eliciting their apoptosis after infection. Previously, we reported that HSV-2 activates the splicing of the mRNA of XBP1, which is related to the activity of the unfolded protein response (UPR) factor Inositol-Requiring Enzyme 1 alpha (IRE-1α). Here, we sought to evaluate if the activation of the IRE-1α pathway in DCs upon HSV infection may be related to impaired DC function after infection with HSV-1 or HSV-2. Interestingly, the pharmacological inhibition of the endonuclease activity of IRE-1α in HSV-1- and HSV-2-infected DCs significantly reduced apoptosis in these cells and enhanced their capacity to migrate to lymph nodes and activate virus-specific CD4
+ and CD8+ T cells. These findings suggest that the activation of the IRE-1α-dependent UPR pathway in HSV-infected DCs may play a significant role in the negative effects that these viruses exert over these cells and that the modulation of this signaling pathway may be relevant for enhancing the function of DCs upon infection with HSVs. [ABSTRACT FROM AUTHOR]- Published
- 2022
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7. Modulation of Adaptive Immunity and Viral Infections by Ion Channels.
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Bohmwald, Karen, Gálvez, Nicolás M. S., Andrade, Catalina A., Mora, Valentina P., Muñoz, José T., González, Pablo A., Riedel, Claudia A., and Kalergis, Alexis M.
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ION channels ,VIRUS diseases ,ADAPTIVE modulation ,CELL physiology ,VIRAL proteins - Abstract
Most cellular functions require of ion homeostasis and ion movement. Among others, ion channels play a crucial role in controlling the homeostasis of anions and cations concentration between the extracellular and intracellular compartments. Calcium (Ca
2+ ) is one of the most relevant ions involved in regulating critical functions of immune cells, allowing the appropriate development of immune cell responses against pathogens and tumor cells. Due to the importance of Ca2+ in inducing the immune response, some viruses have evolved mechanisms to modulate intracellular Ca2+ concentrations and the mobilization of this cation through Ca2+ channels to increase their infectivity and to evade the immune system using different mechanisms. For instance, some viral infections require the influx of Ca2+ through ionic channels as a first step to enter the cell, as well as their replication and budding. Moreover, through the expression of viral proteins on the surface of infected cells, Ca2+ channels function can be altered, enhancing the pathogen evasion of the adaptive immune response. In this article, we review those ion channels and ion transporters that are essential for the function of immune cells. Specifically, cation channels and Ca2+ channels in the context of viral infections and their contribution to the modulation of adaptive immune responses. [ABSTRACT FROM AUTHOR]- Published
- 2021
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8. Induction of Protective Immunity by a Single Low Dose of a Master Cell Bank cGMP-rBCG-P Vaccine Against the Human Metapneumovirus in Mice.
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Soto, Jorge A., Gálvez, Nicolás M. S., Pacheco, Gaspar A., Canedo-Marroquín, Gisela, Bueno, Susan M., and Kalergis, Alexis M.
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IMMUNOGLOBULINS ,HUMORAL immunity ,PLASMA cells ,IMMUNITY ,T cells ,ALVEOLAR macrophages ,B cells - Abstract
Human metapneumovirus (hMPV) is an emergent virus, which mainly infects the upper and lower respiratory tract epithelium. This pathogen is responsible for a significant portion of hospitalizations due to bronchitis and pneumonia in infants and the elderly worldwide. hMPV infection induces a pro-inflammatory immune response upon infection of the host, which is not adequate for the clearance of this pathogen. The lack of knowledge regarding the different molecular mechanisms of infection of this virus has delayed the licensing of effective treatments or vaccines. As part of this work, we evaluated whether a single and low dose of a recombinant Mycobacterium bovis Bacillus Calmette-Guérin (BCG) expressing the phosphoprotein of hMPV (rBCG-P) can induce a protective immune response in mice. Immunization with the rBCG-P significantly decreased neutrophil counts and viral loads in the lungs of infected mice at different time points. This immune response was also associated with a modulated infiltration of innate cells into the lungs, such as interstitial macrophages (IM) and alveolar macrophages (AM), activated CD4
+ and CD8+ T cells, and changes in the population of differentiated subsets of B cells, such as marginal zone B cells and plasma cells. The humoral immune response induced by the rBCG-P led to an early and robust IgA response and a late and constant IgG response. Finally, we determined that the transfer of cells or sera from immunized and infected mice to naïve mice promoted an efficient viral clearance. Therefore, a single and low dose of rBCG-P can protect mice from the disease caused by hMPV, and this vaccine could be a promising candidate for future clinical trials. [ABSTRACT FROM AUTHOR]- Published
- 2021
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9. A Mineralocorticoid Receptor Deficiency in Myeloid Cells Reduces Liver Steatosis by Impairing Activation of CD8+ T Cells in a Nonalcoholic Steatohepatitis Mouse Model.
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Muñoz-Durango, Natalia, Arrese, Marco, Hernández, Alejandra, Jara, Evelyn, Kalergis, Alexis M., and Cabrera, Daniel
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MINERALOCORTICOID receptors ,LIVER cells ,INFLAMMATION ,T cells ,NON-alcoholic fatty liver disease ,NUTRITIONALLY induced diseases - Abstract
Background and Aims: The mineralocorticoid receptor (MR) and renin-angiotensin-aldosterone system (RAAS) are implicated in non-alcoholic liver fatty disease (NALFD). However, inflammatory mechanisms linking MR and RAAS with disease pathology remain unclear. Here we aimed to evaluate the contribution of myeloid MR to the inflammatory response in an animal model of non-alcoholic steatohepatitis (NASH), induced with a methionine-choline deficient diet (MCD). Methods: Mice with a conditional deficiency of MR in myeloid cells (MyMRKO) and their counterpart floxed control mice (FC) were fed for 18 days with MCD or chow diet, respectively. Serum levels of aminotransferases and aldosterone levels were measured and hepatic steatosis, inflammation and fibrosis scored histologically. Hepatic triglyceride content (HTC) and hepatic mRNA levels of pro-inflammatory pro-fibrotic-associated genes were also assessed. Deep flow cytometric analysis was used to dissect the immune response during NASH development. Results: MyMRKO mice fed with an MCD diet exhibited reduced hepatic inflammation and lower HTC than controls. Absolute number and percentage of liver inflammatory infiltrate cells (except for CD8
+ T lymphocytes) were similar in both MyMRKO and control mice fed with an MCD diet but expression of the costimulatory molecule CD86 by dendritic cells and the CD25 activation marker in CD8+ T cells were significantly reduced in MyMRKO. Conclusions: Proinflammatory cells are functionally suppressed in the absence of MR. We hypothesized that loss of MR in myeloid cells reduces lipid accumulation in the liver, in part through modulating the adaptive immune response, which is pivotal for the development of steatosis. [ABSTRACT FROM AUTHOR]- Published
- 2020
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10. Current Insights in the Development of Efficacious Vaccines Against RSV.
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Soto, Jorge A., Stephens, Laura M., Waldstein, Kody A., Canedo-Marroquín, Gisela, Varga, Steven M., and Kalergis, Alexis M.
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VACCINE development ,PULMONARY eosinophilia ,HUMAN metapneumovirus infection ,RESPIRATORY syncytial virus infections ,T helper cells ,IMMUNOREGULATION ,CYTOTOXIC T cells - Abstract
Keywords: Respiratory Syncytial Virus; treatments; vaccines; antibodies; T cells EN Respiratory Syncytial Virus treatments vaccines antibodies T cells 1 5 5 07/22/20 20200717 NES 200717 Introduction Respiratory viral infections are one of the most important global public health burdens, resulting in millions of hospitalizations worldwide annually ([1], [2]). Due to prolonged concerns about vaccine safety, a better understanding of RSV-induced pathogenesis and the host immune response is needed to aid in the development of safe and effective treatments and vaccines for RSV. RSV Vaccine Modalities and Lessons From the Host Immune Response Based on the knowledge gained from the unsuccessful FI-RSV vaccine trial, new vaccine formulations are being developed that promote neutralizing antibodies, induce activated memory and lung-resident CD8 SP + sp T cells, and can be administered to different target populations including children, elderly and pregnant women. Intramuscular and intranasal delivery of the vaccine to healthy adults was well tolerated and induced both RSV-specific antibody titers and RSV-specific CD4 and CD8 SP + sp T cells ([29]-[31]). [Extracted from the article]
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- 2020
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11. Contribution of IDO to human respiratory syncytial virus infection.
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Benavente, Felipe M., Soto, Jorge A., Pizarro‐Ortega, Magdalena S., Bohmwald, Karen, González, Pablo A., Bueno, Susan M., and Kalergis, Alexis M.
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RESPIRATORY syncytial virus infections ,TRYPTOPHAN ,ESSENTIAL amino acids ,T cells ,RESPIRATORY syncytial virus ,CELL physiology - Abstract
IDO is an enzyme that participates in the degradation of tryptophan (Trp), which is an essential amino acid necessary for vital cellular processes. The degradation of Trp and the metabolites generated by the enzymatic activity of IDO can have immunomodulating effects, notably over T cells, which are particularly sensitive to the absence of Trp and leads to the inhibition of T cell activation, cell death, and the suppression of T cell effector functions. Noteworthy, T cells participate in the cellular immune response against the human respiratory syncytial virus (hRSV) and are essential for viral clearance, as well as the total recovery of the host. Furthermore, inadequate or non‐optimal polarization of T cells is often seen during the acute phase of the disease caused by this pathogen. Here, we discuss the capacity of hRSV to exploit the immunosuppressive features of IDO to reduce T cell function, thus acquiring relevant aspects during the biology of the virus. Additionally, we review studies on the influence of IDO over T cell activation and its relationship with hRSV infection. [ABSTRACT FROM AUTHOR]
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- 2019
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12. A Herpes Simplex Virus Type 2 Deleted for Glycoprotein D Enables Dendritic Cells to Activate CD4+ and CD8+ T Cells.
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Retamal-Díaz, Angello R., Kalergis, Alexis M., Bueno, Susan M., and González, Pablo A.
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HERPES simplex virus ,ENCEPHALITIS ,T cells - Abstract
Herpes simplex virus type 2 (HSV-2) is highly prevalent in the human population producing significant morbidity, mainly because of the generation of genital ulcers and neonatal encephalitis. Additionally, HSV-2 infection significantly increases the susceptibility of the host to acquire HIV and promotes the shedding of the latter in the coinfected. Despite numerous efforts to create a vaccine against HSV-2, no licensed vaccines are currently available. A long-standing strategy, based on few viral glycoproteins combined with adjuvants, recently displayed poor results in a Phase III clinical study fueling exploration on the development of mutant HSV viruses that are attenuated in vivo and elicit protective adaptive immune components, such as antiviral antibodies and T cells. Importantly, such specialized antiviral immune components are likely induced and modulated by dendritic cells, professional antigen presenting cells that process viral antigens and present them to T cells. However, HSV interferes with several functions of DCs and ultimately induces their death. Here, we propose that for an attenuated mutant virus to confer protective immunity against HSV in vivo based on adaptive immune components, such virus should also be attenuated in dendritic cells to promote a robust and effective antiviral response. We provide a background framework for this idea, considerations, as well as the means to assess this hypothesis. Addressing this hypothesis may provide valuable insights for the development of novel, safe, and effective vaccines against herpes simplex viruses. [ABSTRACT FROM AUTHOR]
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- 2017
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13. Aberrant T cell immunity triggered by human Respiratory Syncytial Virus and human Metapneumovirus infection.
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González, Andrea E., Lay, Margarita K., Jara, Evelyn L., Espinoza, Janyra A., Gómez, Roberto S., Soto, Jorge, Rivera, Claudia A., Abarca, Katia, Bueno, Susan M., Riedel, Claudia A., and Kalergis, Alexis M.
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T cells ,RESPIRATORY syncytial virus ,CELLULAR immunity ,B cells ,IMMUNE response - Abstract
Human Respiratory syncytial virus (hRSV) and human metapneumovirus (hMPV) are the two major etiological viral agents of lower respiratory tract diseases, affecting mainly infants, young children and the elderly. Although the infection of both viruses trigger an antiviral immune response that mediate viral clearance and disease resolution in immunocompetent individuals, the promotion of long-term immunity appears to be deficient and reinfection are common throughout life. A possible explanation for this phenomenon is that hRSV and hMPV, can induce aberrant T cell responses, which leads to exacerbated lung inflammation and poor T and B cell memory immunity. The modulation of immune response exerted by both viruses include different strategies such as, impairment of immunological synapse mediated by viral proteins or soluble factors, and the induction of pro-inflammatory cytokines by epithelial cells, among others. All these viral strategies contribute to the alteration of the adaptive immunity in order to increase the susceptibility to reinfections. In this review, we discuss current research related to the mechanisms underlying the impairment of T and B cell immune responses induced by hRSV and hMPV infection. In addition, we described the role each virulence factor involved in immune modulation caused by these viruses. [ABSTRACT FROM AUTHOR]
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- 2017
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14. Interleukin-10 Production by T and B Cells Is a Key Factor to Promote Systemic Salmonella enterica Serovar Typhimurium Infection in Mice.
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Salazar, Geraldyne A., Peñaloza, Hernán F., Pardo-Roa, Catalina, Schultz, Bárbara M., Muñoz-Durango, Natalia, Gómez, Roberto S., Salazar, Francisco J., Pizarro, Daniela P., Riedel, Claudia A., González, Pablo A., Alvarez-Lobos, Manuel, Kalergis, Alexis M., and Bueno, Susan M.
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SALMONELLA enterica serovar typhimurium ,MOUSE diseases ,MACROPHAGES - Abstract
Salmonella enterica serovar Typhimurium (S. Typhimurium) is a Gram-negative bacterium that produces disease in numerous hosts. In mice, oral inoculation is followed by intestinal colonization and subsequent systemic dissemination, which leads to severe pathogenesis without the activation of an efficient anti-Salmonella immune response. This feature suggests that the infection caused by S. Typhimurium may promote the production of anti-inflammatory molecules by the host that prevent efficient T cell activation and bacterial clearance. In this study, we describe the contribution of immune cells producing the anti-inflammatory cytokine interleukin-10 (IL-10) to the systemic infection caused by S. Typhimurium in mice. We observed that the production of IL-10 was required by S. Typhimurium to cause a systemic disease, since mice lacking IL-10 (IL-10-/-) were significantly more resistant to die after an infection as compared to wild-type (WT) mice. IL-10-/- mice had reduced bacterial loads in internal organs and increased levels of pro-inflammatory cytokines in serum at 5 days of infection. Importantly, WT mice showed high bacterial loads in tissues and no increase of cytokines in serum after 5 days of S. Typhimurium infection, except for IL-10. In WT mice, we observed a peak of il-10 messenger RNA production in ileum, spleen, and liver after 5 days of infection. Importantly, the adoptive transfer of T or B cells from WT mice restored the susceptibility of IL-10-/- mice to systemic S. Typhimurium infection, suggesting that the generation of regulatory cells in vivo is required to sustain a systemic infection by S. Typhimurium. These findings support the notion that IL-10 production from lymphoid cells is a key process in the infective cycle of S. Typhimurium in mice due to generation of a tolerogenic immune response that prevents bacterial clearance and supports systemic dissemination. [ABSTRACT FROM AUTHOR]
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- 2017
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15. Immunological Features of Respiratory Syncytial Virus-Caused Pneumonia--Implications for Vaccine Design.
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Rey-Jurado, Emma and Kalergis, Alexis M.
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RESPIRATORY syncytial virus infections , *VIRAL pneumonia , *BRONCHIOLITIS , *VACCINES , *EPITHELIAL cells , *T cells , *DISEASE risk factors , *PREVENTION , *THERAPEUTICS , *DISEASES ,RESPIRATORY insufficiency treatment - Abstract
The human respiratory syncytial virus (hRSV) is the causative agent for high rates of hospitalizations due to viral bronchiolitis and pneumonia worldwide. Such a disease is characterized by an infection of epithelial cells of the distal airways that leads to inflammation and subsequently to respiratory failure. Upon infection, different pattern recognition receptors recognize the virus and trigger the innate immune response against the hRSV. Further, T cell immunity plays an important role for virus clearance. Based on animal studies, it is thought that the host immune response to hRSV is based on a biased T helper (Th)-2 and Th17 T cell responses with the recruitment of T cells, neutrophils and eosinophils to the lung, causing inflammation and tissue damage. In contrast, human immunity against RSV has been shown to be more complex with no definitive T cell polarization profile. Nowadays, only a humanized monoclonal antibody, known as palivizumab, is available to protect against hRSV infection in high-risk infants. However, such treatment involves several injections at a significantly high cost. For these reasons, intense research has been focused on finding novel vaccines or therapies to prevent hRSV infection in the population. Here, we comprehensively review the recent literature relative to the immunological features during hRSV infection, as well as the new insights into preventing the disease caused by this virus. [ABSTRACT FROM AUTHOR]
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- 2017
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16. Human metapneumovirus keeps dendritic cells from priming antigen-specific naive T cells.
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Céspedes, Pablo F., Gonzalez, Pablo A., and Kalergis, Alexis M.
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RNA viruses ,DENDRITIC cells ,T cells ,RESPIRATORY infections in children ,ANTIGENIC variation ,INTERLEUKIN-2 ,RESPIRATORY syncytial virus - Abstract
Human metapneumovirus (h MPV) is the second most common cause of acute lower respiratory tract infections in children, causing a significant public health burden worldwide. Given that h MPV can repeatedly infect the host without major antigenic changes, it has been suggested that h MPV may have evolved molecular mechanisms to impair host adaptive immunity and, more specifically, T-cell memory. Recent studies have shown that h MPV can interfere with superantigen-induced T-cell activation by infecting conventional dendritic cells ( DCs). Here, we show that h MPV infects mouse DCs in a restricted manner and induces moderate maturation. Nonetheless, h MPV-infected DCs are rendered inefficient at activating naive antigen-specific CD4
+ T cells ( OT-II), which not only display reduced proliferation, but also show a marked reduction in surface activation markers and interleukin-2 secretion. Decreased T-cell activation was not mediated by interference with DC-T-cell immunological synapse formation as recently described for the human respiratory syncytial virus (hRSV), but rather by soluble factors secreted by h MPV-infected DCs. These data suggest that although h MPV infection is restricted within DCs, it is sufficient to interfere with their capacity to activate naive T cells. Altogether, by interfering with DC function and productive priming of antigen-inexperienced T cells, h MPV could impair the generation of long-term immunity. [ABSTRACT FROM AUTHOR]- Published
- 2013
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17. Modulation of Tumor Immunity by Soluble and Membrane-Bound Molecules at the Immunological Synapse.
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González, Pablo A., Carreño, Leandro J., Céspedes, Pablo F., Bueno, Susan M., Riedel, Claudia A., and Kalergis, Alexis M.
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T cells ,LYMPHOCYTES ,MEMBRANE proteins ,TUMOR growth ,IMMUNE system - Abstract
To circumvent pathology caused by infectious microbes and tumor growth, the host immune system must constantly clear harmful microorganisms and potentially malignant transformed cells. This task is accomplished in part by T-cells, which can directly kill infected or tumorigenic cells. Acrucial event determining the recognition and elimination of detrimental cells is antigen recognition by the T cell receptor (TCR) expressed on the surface of T cells. Upon binding of the TCR to cognate peptide-MHC complexes presented on the surface of antigen presenting cells (APCs), a specialized supramolecular structure known as the immunological synapse (IS) assembles at the T cell-APC interface. Such a structure involves massive redistribution of membrane proteins, including TCR/pMHC complexes, modulatory receptor pairs, and adhesion molecules. Furthermore, assembly of the immunological synapse leads to intracellular events that modulate and define the magnitude and characteristics of the T cell response. Here, we discuss recent literature on the regulation and assembly of IS and the mechanisms evolved by tumors to modulate its function to escape T cell cytotoxicity, as well as novel strategies targeting the IS for therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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18. IgG keeps virulent Salmonella from evading dendritic cell uptake.
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Riquelme, Sebastián A., Bueno, Susan M., and Kalergis, Alexis M.
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DENDRITIC cells ,IMMUNOGLOBULIN G ,CYTOSKELETON ,SALMONELLA ,T cells ,PHOSPHATIDYLINOSITOL 3-kinases - Abstract
Dendritic cells (DCs) are phagocytic professional antigen-presenting cells that can prime naive T cells and initiate anti-bacterial immunity. However, several pathogenic bacteria have developed virulence mechanisms to impair DC function. For instance, Salmonella enterica serovar Typhimurium can prevent DCs from activating antigen-specific T cells. In addition, it has been described that the Salmonella Pathogenicity Island 1 (SPI-1), which promotes phagocytosis of bacteria in non-phagocytic cells, can suppress this process in DCs in a phosphatidylinositol 3-kinase (PI3K) -dependent manner. Both mechanisms allow Salmonella to evade host adaptive immunity. Recent studies have shown that IgG-opsonization of Salmonella can restore the capacity of DCs to present antigenic peptide-MHC complexes and prime T cells. Interestingly, T-cell activation requires Fcγ receptor III (FcγRIII) expression over the DC surface, suggesting that this receptor could counteract both antigen presentation and phagocytosis evasion by bacteria. We show that, despite IgG-coated Salmonella retaining its capacity to secrete anti-capture proteins, DCs are efficiently capable of engulfing a large number of IgG-coated bacteria. These results suggest that DCs employ another mechanism to engulf IgG-coated Salmonella, different from that used for free bacteria. In this context, we noted that DCs do not employ PI3K, actin cytoskeleton or dynamin to capture IgG-coated bacteria. Likewise, we observed that the capture is an FcγR-independent mechanism. Interestingly, these internalized bacteria were rapidly targeted for degradation within lysosomal compartments. Hence, our results suggest a novel mechanism in DCs that does not employ PI3K/actin cytoskeleton/dynamin/FcγRs to engulf IgG-coated Salmonella, is not affected by anti-capture SPI-1-derived effectors and enhances DC immunogenicity, bacterial degradation and antigen presentation. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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19. T-cell antagonism by short half-life pMHC ligands can be mediated by an efficient trapping of T-cell polarization toward the APC.
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Carreño, Leandro J., Riquelme, Erick M., González, Pablo A., Espagnolle, Nicolas, Riedel, Claudia A., Valitutti, Salvatore, and Kalergis, Alexis M.
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T cells ,CELL receptors ,ANTIGEN presenting cells ,MAJOR histocompatibility complex ,SYNAPSES ,PHOSPHORYLATION - Abstract
T-cell activation results from productive T-cell receptor (TCR) engagement by a cognate peptide-MHC (pMHC) complex on the antigen presenting cell (APC) surface, a process leading to the polarization of the T-cell secretory machinery toward the APC in- terface. We have previously shown that the half-life of the TCR/pMHC interaction and the density of pMHC on the APC are two parameters determining T-cell activation. However, whether the half-life of the TCR/pMHC interaction can modulate the efficiency of T-cell secretory machinery polarization toward an APC still remains unclear. Here, by using altered peptide ligands conferring different half-lives to the TCR/pMHC interaction, we have tested how this parameter can control T-cell polarization. We observed that only TCR/pMHC interactions with intermediate half-lives can promote the assembly of synapses that lead to T-cell activation. Strikingly, intermediate half-life interactions can be competed out by short half-life interactions, which can efficiently promote 1-cell polarization and antagonize T-cell activation that was induced by activating intermediate half-life interactions. However, short TCR/pMHC interactions fail at promoting phosphorylation of signaling molecules at the T-cell-APC contact interface, which are needed for T-cell activation. Our data suggest that although intermediate half-life pMHC ligands promote assembly of activating synapses, this process can be inhibited by short half-life antagonistic pMHC ligands, which promote the assembly of non activating synapses. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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20. Protective T cell immunity against respiratory syncytial virus is efficiently induced by recombinant BCG.
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Bueno, Susan M., Gonzâlez, Pablo A., Cautivo, Kelly M., Mora, Jorge E., Leiva, Eduardo D., Tobar, Hugo E., Fennelly, Glenn J., Eugenin, Eliseo A., Jacobs Jr, William R., Riedel, Claudia A., and Kalergis, Alexis M.
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T cells ,LYMPHOCYTES ,IMMUNE response ,RESPIRATORY syncytial virus ,PARAMYXOVIRUSES - Abstract
Respiratory syncytial virus (RSV) is one of the leading causes of childhood hospitalization and a major health burden worldwide. Unfortunately, because of an inefficient immunological memory, RSV infection provides limited immune protection against reinfection. Furthermore, RSV can induce an inadequate Th2-type immune response that causes severe respiratory tract inflammation and obstruction. It is thought that effective RSV clearance requires the induction of balanced Th1-type immunity, involving the activation of IFN-γ-secreting cytotoxic T cells. A recognized inducer of Th1 immunity is Mycobacterium bovis bacillus Calmette-Guérin (BCG), which has been used in newborns for decades in several countries as a tuberculosis vaccine. Here, we show that immunization with recombinant BCG strains expressing RSV antigens promotes protective Th1-type immunity against RSV in mice. Activation of RSV-specific T cells producing IFN-γ and IL-2 was efficiently obtained after immunization with recombinant BCG. This type of T cell immunity was protective against RSV challenge and caused a significant reduction of inflammatory cell infiltration in the airways. Furthermore, mice immunized with recombinant BCG showed no weight loss and reduced lung viral loads. These data strongly support recombinant BCG as an efficient vaccine against RSV because of its capacity to promote protective Th1 immunity. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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21. Contribution of Dysregulated DNA Methylation to Autoimmunity.
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Funes, Samanta C., Fernández-Fierro, Ayleen, Rebolledo-Zelada, Diego, Mackern-Oberti, Juan P., and Kalergis, Alexis M.
- Subjects
DNA methylation ,SYSTEMIC lupus erythematosus ,THERAPEUTICS ,AUTOIMMUNITY ,T cells ,AUTOIMMUNE diseases ,EPIGENOMICS - Abstract
Epigenetic mechanisms, such as DNA methylation, histone modifications, and non-coding RNAs are known regulators of gene expression and genomic stability in cell growth, development, and differentiation. Because epigenetic mechanisms can regulate several immune system elements, epigenetic alterations have been found in several autoimmune diseases. The purpose of this review is to discuss the epigenetic modifications, mainly DNA methylation, involved in autoimmune diseases in which T cells play a significant role. For example, Rheumatoid Arthritis and Systemic Lupus Erythematosus display differential gene methylation, mostly hypomethylated 5′-C-phosphate-G-3′ (CpG) sites that may associate with disease activity. However, a clear association between DNA methylation, gene expression, and disease pathogenesis must be demonstrated. A better understanding of the impact of epigenetic modifications on the onset of autoimmunity will contribute to the design of novel therapeutic approaches for these diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
22. The capacity of Salmonella to survive inside dendritic cells and prevent antigen presentation to T cells is host specific.
- Author
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Bueno, Susan M., González, Pablo A., Carreño, Leandro J., Tobar, Jaime A., Mora, Guido C., Pereda, Cristian J., Salazar-Onfray, Flavio, and Kalergis, Alexis M.
- Subjects
DENDRITIC cells ,SALMONELLA ,T cells ,IMMUNOGLOBULINS ,BACTERIAL antigens ,IMMUNE response - Abstract
Infection with Salmonella enterica serovar Typhimurium ( S. Typhimurium) causes a severe and lethal systemic disease in mice, characterized by poor activation of the adaptive immune response against Salmonella-derived antigens. Recently, we and others have reported that this feature relies on the ability of S. Typhimurium to survive within murine dendritic cells (DCs) and avoid the presentation of bacteria-derived antigens to T cells. In contrast, here we show that infection of murine DCs with either S. Typhi or S. Enteritidis, two serovars adapted to different hosts, leads to an efficient T-cell activation both in vitro and in vivo. Accordingly, S. Typhi and S. Enteritidis failed to replicate within murine DCs and were quickly degraded, allowing T-cell activation. In contrast, human DCs were found to be permissive for survival and proliferation of S. Typhi, but not for S. Typhimurium or S. Enteritidis. Our data suggest that Salmonella host restriction is characterized by the ability of these bacteria to survive within DCs and avoid activation of the adaptive immune response in their specific hosts. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
23. Injury of skeletal muscle and specific cytokines induce the expression of gap junction channels in mouse dendritic cells.
- Author
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Corvalán, Liliana A., Araya, Roberto, Brañes, Mariá C., Sáez, Pablo J., Kalergis, Alexis M., Tobar, Jaime A., Theis, Martin, Willecke, Klaus, and Sáez, Juan C.
- Subjects
MUSCULOSKELETAL system diseases ,CYTOKINES ,CONNEXINS ,DENDRITIC cells ,T cells - Abstract
Dendritic cells (DCs) in culture express at least connexin43, a protein subunit of gap junctions, and form gap junction channels, which could be important for T-cells activation. Here, we evaluated whether DCs express connexins in vivo and also to identify components of their microenvironment that regulate the functional expression of gap junctions. In vivo studies were performed in lymph nodes of mice under control conditions or after skeletal muscle damage. In double immunolabeling studies, connexin45 was frequently detected in DEC205
+ DCs in lymph nodes of control animals, whereas connexin43 was rarely found in DCs. However, connexin43 was upregulated in DCs after skeletal muscle damage. Upregulation of connexin43 gene expression by tissue damage was also confirmed in mice carrying a β-galactosidase reporter gene in a connexin43 allele. The effect of several cytokines on the expression of functional gap junctions between cultured DCs was also tested. Under control conditions, cultured DCs did not communicate via gap junctions. However, after treatment with keratinocyte-conditioned medium or cytokine mixtures containing at least TNF-α and IL-1β, they became transiently coupled through a pathway sensitive to octanol, a gap junction blocker. Cellular coupling induced by effective cytokine mixtures was prevented by IL-6. Single cytokines (TNF-α, IL-1β, IFN-γ, or IL-6) or other mixtures than the described above did not induce coupling via gap junctions. Increased levels of connexin43 and connexin45 protein and mRNA accompanied the appearance of cellular coupling. These studies provide demonstration of connexin expression and regulation by specific danger signals in DCs. J. Cell. Physiol. 211: 649–660, 2007. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]- Published
- 2007
- Full Text
- View/download PDF
24. The half-life of the T-cell receptor/peptide–major histocompatibility complex interaction can modulate T-cell activation in response to bacterial challenge.
- Author
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Carreño, Leandro J., Bueno, Susan M., Bull, Paulina, Nathenson, Stanley G., and Kalergis, Alexis M.
- Subjects
T cell receptors ,HALF-life (Nuclear physics) ,PEPTIDES ,DENDRITIC cells ,MICROBIOLOGY - Abstract
T-cell activation results from engagement of the T-cell receptor (TCR) by cognate peptide–major histocompatibility complex (pMHC) complexes on the surface of antigen-presenting cells (APC). Previous studies have provided evidence supporting the notion that the half-life of the TCR/pMHC interaction and the density of pMHC on the APC are two parameters that can influence T-cell activation. However, whether the half-life of the TCR/pMHC interaction can modulate T-cell activation in response to a pathogen challenge remains unknown. To approach this question, we generated strains of bacteria expressing variants of the ovalbumin (OVA) antigen, carrying point mutations in the SIINFEKL sequence. When bound to H-2K
b , this peptide is the cognate ligand for the OT-I TCR. Variants of the H-2Kb /SIINFEKL bind to the OT-I TCR with distinct half-lives. Here we show that dendritic cells (DCs) infected with bacteria expressing OVA variants were incapable of activating OT-I T cells when the half-life of the TCR/H-2Kb /OVA interaction was excessively short. Consistent with these data, T-cell activation was only observed in mice infected with bacteria expressing OVA variants that bound to OT-I with a half-life above a certain threshold. Considered together, our data suggest that the half-life of TCR/pMHC interaction can significantly modulate T-cell activation in vivo, as well as influence recognition of antigens expressed by bacteria. These observations underscore the importance of the TCR/pMHC half-life on the clearance of pathogens. [ABSTRACT FROM AUTHOR]- Published
- 2007
- Full Text
- View/download PDF
25. Activated TCRs remain marked for internalization after dissociation from pMHC.
- Author
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Coombs, Daniel, Kalergis, Alexis M., Nathenson, Stanley G., Wofsy, Carla, and Goldstein, Byron
- Subjects
- *
T cells , *MAJOR histocompatibility complex - Abstract
To assess the roles of serial engagement and kinetic proofreading in T cell receptor (TCR) internalization, we have developed a mathematical model of this process. Our determination of TCR down-regulation for an array of TCR mutants, interpreted in the context of the model, has provided new information about peptide-induced TCR internalization. The amount of TCR down-regulation increases to a maximum value and then declines as a function of the half-life of the bond between the TCR and peptide–major histocompatibility complex (pMHC). The model shows that this behavior, which reflects competition between serial engagement and kinetic proofreading, arises only if it is postulated that activated TCRs remain marked for internalization after dissociation from pMHC. The model also predicts that because of kinetic proofreading, the range of TCR-pMHC–binding half-lives required for T cell activation depends on the concentrations and localization of intracellular signaling molecules. We show here that kinetic proofreading provides an explanation for the different requirements for activation observed in naïve and memory T cells. [ABSTRACT FROM AUTHOR]
- Published
- 2002
- Full Text
- View/download PDF
26. Julis Marmur Award Lecture.
- Author
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Kalergis, Alexis M. and Nathenson, Stanley G.
- Subjects
- *
T cells , *IMMUNE response - Abstract
Examines the importance of alpha beta T cells in the immune surveillance against infectious agents and endogenous malignant cell growth. Mechanism of antigen-specificity of the alpha beta T cell receptor; Activation of self-reactive T cells and development of autoimmunity; Components of the innate immune system.
- Published
- 2000
27. CD8+ T Cells Are the Effectors of the Contact Dermatitis Induced by Urushiol in Mice and Are Regulated by CD4+ T Cells.
- Author
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López, Carolina B., Kalergis, Alexis M., Becker, María Inés, Garbarino, Juan A., and De Ioannes, Alfredo E.
- Subjects
- *
CONTACT dermatitis , *SKIN inflammation , *T cells , *URUSHIOL , *ALLERGENS , *CATECHOL , *DELAYED hypersensitivity , *LYMPHOCYTES - Abstract
Background: The exposure of human skin to leaves and branches of litre (Lithraea caustica), a Chilean endemic tree, induces a severe contact dermatitis characterized by swelling and pruritus in susceptible individuals. The allergenic priniciple of litre is 3–pentadecyl (10–enyl) catechol (litreol), which is structurally similar to the allergens isolated from poison oak and poison ivy. All of them belong to a family of compounds named urushiols. As a proelectrophilic allergen, litreol must be intracellularly activated before modifying proteins of individuals exposed to it. As a result, self–peptides derived from litreol–modified intracellular proteins would be presented in the context of class I MHC molecules. We hypothesized that CD8+ T lymphocytes would play a major role during the effector phase of the immune response induced by those modified peptides. In order to test this hypothesis, we investigated the cellular immune response to litreol in Balb/cJ mice. The role of the different lymphocyte subpopulations in this response was assessed by immunodepleting mice of CD4+ or CD8+ T lymphocytes using specific monoclonal antibodies (mAbs). We report the observation that the contact dermatitis induced by litreol has two components: a primary response which does not require TCRαβ+ T cells, and a secondary response mediated mainly by CD8+ T cells and regulated by CD4+ T cells. Our results show that CD8+ lymphocytes play a central role as effectors of the secondary response to litreol. Furthermore, our data suggest that two functionally different CD4+ T subpopulations serve as regulators of the CD8+ T cell function: a CD4+ T helper population sensitive to a low dose of the depleting mAb, and CD4+ T suppressor population which is eliminated only with a high dose of depleting mAb. [ABSTRACT FROM AUTHOR]
- Published
- 1998
- Full Text
- View/download PDF
28. TCR Repertoire Characterization for T Cells Expanded in Response to hRSV Infection in Mice Immunized with a Recombinant BCG Vaccine.
- Author
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Rey-Jurado, Emma, Bohmwald, Karen, Correa, Hernán G., and Kalergis, Alexis M.
- Subjects
BCG vaccines ,T cell receptors ,T cells ,NEUTROPHILS ,TH1 cells ,RESPIRATORY syncytial virus ,CELL populations ,VIRUS diseases - Abstract
T cells play an essential role in the immune response against the human respiratory syncytial virus (hRSV). It has been described that both CD4
+ and CD8+ T cells can contribute to the clearance of the virus during an infection. However, for some individuals, such an immune response can lead to an exacerbated and detrimental inflammatory response with high recruitment of neutrophils to the lungs. The receptor of most T cells is a heterodimer consisting of α and β chains (αβTCR) that upon antigen engagement induces the activation of these cells. The αβTCR molecule displays a broad sequence diversity that defines the T cell repertoire of an individual. In our laboratory, a recombinant Bacille Calmette–Guérin (BCG) vaccine expressing the nucleoprotein (N) of hRSV (rBCG-N-hRSV) was developed. Such a vaccine induces T cells with a Th1 polarized phenotype that promote the clearance of hRSV infection without causing inflammatory lung damage. Importantly, as part of this work, the T cell receptor (TCR) repertoire of T cells expanded after hRSV infection in naïve and rBCG-N-hRSV-immunized mice was characterized. A more diverse TCR repertoire was observed in the lungs from rBCG-N-hRSV-immunized as compared to unimmunized hRSV-infected mice, suggesting that vaccination with the recombinant rBCG-N-hRSV vaccine triggers the expansion of T cell populations that recognize more viral epitopes. Furthermore, differential expansion of certain TCRVβ chains was found for hRSV infection (TCRVβ+ 8.3 and TCRVβ+ 5.1,5.2) as compared to rBCG-N-hRSV vaccination (TCRVβ+ 11 and TCRVβ+ 12). Our findings contribute to better understanding the T cell response during hRSV infection, as well as the functioning of a vaccine that induces a protective T cell immunity against this virus. [ABSTRACT FROM AUTHOR]- Published
- 2020
- Full Text
- View/download PDF
29. Contribution of Resident Memory CD8+ T Cells to Protective Immunity against Respiratory Syncytial Virus and Their Impact on Vaccine Design.
- Author
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Retamal-Díaz, Angello, Covián, Camila, Pacheco, Gaspar A., Castiglione-Matamala, Angelo T., Bueno, Susan M., González, Pablo A., and Kalergis, Alexis M.
- Subjects
RESPIRATORY syncytial virus ,VIRAL vaccines ,T cells ,RESPIRATORY infections ,VACCINE effectiveness ,CHILD mortality ,VIRUS diseases - Abstract
Worldwide, human respiratory syncytial virus (RSV) is the most common etiological agent for acute lower respiratory tract infections (ALRI). RSV-ALRI is the major cause of hospital admissions in young children, and it can cause in-hospital deaths in children younger than six months old. Therefore, RSV remains one of the pathogens deemed most important for the generation of a vaccine. On the other hand, the effectiveness of a vaccine depends on the development of immunological memory against the pathogenic agent of interest. This memory is achieved by long-lived memory T cells, based on the establishment of an effective immune response to viral infections when subsequent exposures to the pathogen take place. Memory T cells can be classified into three subsets according to their expression of lymphoid homing receptors: central memory cells (T
CM ), effector memory cells (TEM ) and resident memory T cells (TRM ). The latter subset consists of cells that are permanently found in non-lymphoid tissues and are capable of recognizing antigens and mounting an effective immune response at those sites. TRM cells activate both innate and adaptive immune responses, thus establishing a robust and rapid response characterized by the production of large amounts of effector molecules. TRM cells can also recognize antigenically unrelated pathogens and trigger an innate-like alarm with the recruitment of other immune cells. It is noteworthy that this rapid and effective immune response induced by TRM cells make these cells an interesting aim in the design of vaccination strategies in order to establish TRM cell populations to prevent respiratory infectious diseases. Here, we discuss the biogenesis of TRM cells, their contribution to the resolution of respiratory viral infections and the induction of TRM cells, which should be considered for the rational design of new vaccines against RSV. [ABSTRACT FROM AUTHOR]- Published
- 2019
- Full Text
- View/download PDF
30. Contribution of sex steroids and prolactin to the modulation of T and B cells during autoimmunity.
- Author
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Recalde, Gabriela, Moreno-Sosa, Tamara, Yúdica, Florencia, Quintero, Cristian A., Sánchez, María Belén, Jahn, Graciela A., Kalergis, Alexis M., and Mackern-Oberti, Juan Pablo
- Subjects
- *
STEROIDS , *PROLACTIN , *T cells , *B cells , *AUTOIMMUNITY - Abstract
In this review we discuss how sex steroids and prolactin affect regulation and responsiveness of B and T cells. Sex hormones exert profound effects on several physiological processes of non- reproductive tissues. In the immune system, several studies with experimental models for SLE have shown a noticeable pro-inflammatory role for ERα, contributing to disease development reflected in proteinuria and renal pathology. On the other hand, ERβ appears to have an anti- inflammatory and immunosuppressive effect. Estrogen/ERα signaling induced an increase of Th17 cells in lymph nodes as well as the expression of its correspondent chemokine receptor CCR6 during collagen induced arthritis acute phase. High levels of anti- DNA antibodies and increased mortality was observed when given high E and prolactin doses to NZB/NZW mice, as compared with mice receiving low E and prolactin doses, or high E and low prolactin doses. Intracellular progesterone receptors have been detected in TCD4 + cells but in contrast as observed with ERs, it suppresses T cell dependent responses. Progestagen administration on female NZB/NZW mice decreased anti DNA IgG, improved survival, decreased glomerulonephritis and proteinuria. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
31. A single, low dose of a cGMP recombinant BCG vaccine elicits protective T cell immunity against the human respiratory syncytial virus infection and prevents lung pathology in mice.
- Author
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Céspedes, Pablo F., Rey-Jurado, Emma, Espinoza, Janyra A., Rivera, Claudia A., Canedo-Marroquín, Gisela, Bueno, Susan M., and Kalergis, Alexis M.
- Subjects
- *
RESPIRATORY syncytial virus infections , *BRONCHIOLITIS , *BCG vaccines , *T cells , *HOSPITAL care , *IMMUNOCOMPROMISED patients , *IMMUNOLOGY , *PHYSIOLOGY - Abstract
Human respiratory syncytial virus (hRSV) is a major health burden worldwide, causing the majority of hospitalizations in children under two years old due to bronchiolitis and pneumonia. HRSV causes year-to-year outbreaks of disease, which also affects the elderly and immunocompromised adults. Furthermore, both hRSV morbidity and epidemics are explained by a consistently high rate of re-infections that take place throughout the patient life. Although significant efforts have been invested worldwide, currently there are no licensed vaccines to prevent hRSV infection. Here, we describe that a recombinant Bacillus Calmette-Guerin (BCG) vaccine expressing the nucleoprotein (N) of hRSV formulated under current good manufacture practices (cGMP rBCG-N-hRSV) confers protective immunity to the virus in mice. Our results show that a single dose of the GMP rBCG-N-hRSV vaccine retains its capacity to protect mice against a challenge with a disease-causing infection of 1 × 10 7 plaque-forming units (PFUs) of the hRSV A2 clinical strain 13018-8. Compared to unimmunized infected controls, vaccinated mice displayed reduced weight loss and less infiltration of neutrophils within the airways, as well as reduced viral loads in bronchoalveolar lavages, parameters that are characteristic of hRSV infection in mice. Also, ex vivo re-stimulation of splenic T cells at 28 days post-immunization activated a repertoire of T cells secreting IFN-γ and IL-17, which further suggest that the rBCG-N-hRSV vaccine induced a mixed, CD8 + and CD4 + T cell response capable of both restraining viral spread and preventing damage of the lungs. All these features support the notion that rBCG-N-hRSV is a promising candidate vaccine to be used in humans to prevent the disease caused by hRSV in the susceptible population. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
32. Functional Gap Junctions Accumulate at the Immunological Synapse and Contribute to T Cell Activation.
- Author
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Mendoza-Naranjo, Ariadna, Bouma, Gerben, Pereda, Cristián, Ramírez, Marcos, Webb, Kevin F., Tittarelli, Andrés, López, Mercedes N., Kalergis, Alexis M., Thrasher, Adrian J., Becker, David L., and Salazar-Onfray, Flavio
- Subjects
- *
GAP junctions (Cell biology) , *CELL communication , *DENDRITIC cells , *T cells , *LEUCOCYTES - Abstract
Gap junction (GJ) mediates intercellular communication through linked hemichannels from each of two adjacent cells. Using human and mouse models, we show that connexin 43 (Cx43), the main GJ protein in the immune system, was recruited to the immunological synapse during T cell priming as both GJs and stand-alone hemichannels. Cx43 accumulation at the synapse was Ag specific and time dependent, and required an intact actin cytoskeleton. Fluorescence recovery after photobleaching and Cx43-specific inhibitors were used to prove that intercellular communication between T cells and dendritic cells is bidirectional and specifically mediated by Cx43. Moreover, this intercellular cross talk contributed to T cell activation as silencing of Cx43 with an antisense or inhibition of GJ docking impaired intracellular Ca2+ responses and cytokine release by T cells. These findings identify Cx43 as an important functional component of the immunological synapse and reveal a crucial role for GJs and hemichannels as coordinators of the dendritic cell-T cell signaling machinery that regulates T cell activation. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
33. Host immunity during RSV pathogenesis
- Author
-
Bueno, Susan M., González, Pablo A., Pacheco, Rodrigo, Leiva, Eduardo D., Cautivo, Kelly M., Tobar, Hugo E., Mora, Jorge E., Prado, Carolina E., Zúñiga, Juan P., Jiménez, Jorge, Riedel, Claudia A., and Kalergis, Alexis M.
- Subjects
- *
RESPIRATORY syncytial virus , *IMMUNE response , *NATURAL immunity , *IMMUNOPATHOLOGY , *DENDRITIC cells , *IMMUNOPHARMACOLOGY - Abstract
Abstract: Infection by respiratory syncytial virus (RSV) is the leading cause of childhood hospitalization as well as a major health and economic burden worldwide. Unfortunately, RSV infection provides only limited immune protection to reinfection, mostly due to inadequate immunological memory, which leads to an exacerbated inflammatory response in the respiratory tract promoting airway damage during virus clearance. This exacerbated and inefficient immune-inflammatory response triggered by RSV, has often been attributed to the induction of a Th2-biased immunity specific for some of the RSV antigens. These features of RSV infection suggest that the virus might possess molecular mechanisms to enhance allergic-type immunity in the host in order to prevent clearance by cytotoxic T cells and ensure survival and dissemination to other hosts. In this review, we discuss recent findings that contribute to explain the components of the innate and adaptive immune response that are involved in RSV-mediated disease exacerbation. Further, the virulence mechanisms used by RSV to avoid activation of protective immune responses are described. [Copyright &y& Elsevier]
- Published
- 2008
- Full Text
- View/download PDF
34. T cell immunity evasion by virulent Salmonella enterica
- Author
-
Bueno, Susan M., González, Pablo A., Schwebach, J. Reid, and Kalergis, Alexis M.
- Subjects
- *
FOOD poisoning , *FOODBORNE diseases , *FOOD , *CELLULAR mechanics - Abstract
Abstract: Salmonella enterica are Gram-negative bacteria that cause systemic disease in their specific hosts. One of the recently appreciated features of Salmonella pathogenicity is the capacity of the bacteria to impair host adaptive immunity by interfering with DC function and T cell activation. It is likely that this feature of virulent Salmonella is needed to promote systemic dissemination in the host. Recent studies have suggested explanations for some of the molecular mechanisms developed by virulent Salmonella to impair DC and T cell function. Several of these mechanisms require the expression of virulence genes encoded within Salmonella pathogenicity islands. Targeted deletion of these genes diminishes Salmonella pathogenicity and leads to efficient activation of T cells by Salmonella-infected DCs. In this review, recent data that support the subversion of DC function by Salmonella as a means to evade host adaptive immunity and cause systemic infection are discussed. These new findings suggest a new pathogenesis model with DCs as key targets for Salmonella virulence factors. [Copyright &y& Elsevier]
- Published
- 2007
- Full Text
- View/download PDF
35. Modulation of immunological synapse by membrane-bound and soluble ligands
- Author
-
González, Pablo A., Carreño, Leandro J., Figueroa, Claudio A., and Kalergis, Alexis M.
- Subjects
- *
IMMUNE response , *INFECTION , *TUMOR growth , *ANTIGENS , *IMMUNITY , *IMMUNOLOGY , *MEMBRANE proteins - Abstract
Abstract: An efficient adaptive immune response should prevent pathogen infections and tumor growth without causing significant damage to host constituents. A crucial event determining the balance between tolerance and immunity is antigen recognition by T cells on the surface of antigen presenting cells (APC). Several molecular contacts at the interface between T cells and APCs contribute to define the nature of the adaptive immune response against a particular antigen. Upon TCR engagement by a peptide–MHC complex (pMHC) on the surface of an APC, a specialized supra-molecular structure known as immunological synapse (IS) assembles at the interface between these two cells. This structure involves massive re-distribution of membrane proteins, including TCR and pMHC complexes, as well as co-stimulatory and adhesion molecules. Furthermore, IS assembly leads to several important intracellular events necessary for T cell activation, such as recruitment of signaling molecules and cytoskeleton rearrangements. Because IS assembly leads to major consequences on the function of T cells, several studies have attempted to identify both soluble and membrane-bound molecules that could contribute to modulate the IS function. Here we describe recent literature on the regulation of IS assembly and modulation by TCR/pMHC binding kinetics, chemokines and cytokines focusing on their role at controlling the balance between adaptive immunity and tolerance. [Copyright &y& Elsevier]
- Published
- 2007
- Full Text
- View/download PDF
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