scholarly journals Development of a Secondary Immune Response toMycobacterium tuberculosisIs Independent of Toll-Like Receptor 2

2010 ◽  
Vol 79 (3) ◽  
pp. 1118-1123 ◽  
Author(s):  
Amanda McBride ◽  
Kamlesh Bhatt ◽  
Padmini Salgame
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Host Resistance ◽  
Toll Like Receptor ◽  
Response Phenotype ◽  
Toll Like Receptor 2 ◽  
Antigen Presenting ◽  
Memory Immune Response

ABSTRACTPublished work indicates that the contribution of Toll-like receptor 2 (TLR2) to host resistance during acuteMycobacterium tuberculosisinfection is marginal. However, in these studies, TLR2 participation in the memory immune response toM. tuberculosiswas not determined. The substantialin vitroevidence thatM. tuberculosisstrongly triggers TLR2 on dendritic cells and macrophages to bring about either activation or inhibition of antigen-presenting cell (APC) functions, along with accumulating evidence that memory T cell development can be calibrated by TLR signals, led us to question the role of TLR2 in host resistance to secondary challenge withM. tuberculosis. To address this question, a memory immunity model was employed, and the response of TLR2-deficient (TLR2 knockout [TLR2KO]) mice following a secondary exposure toM. tuberculosiswas compared to that of wild-type (WT) mice based on assessment of the bacterial burden, recall response, phenotype of recruited T cells, and granulomatous response. We found that upon rechallenge withM. tuberculosis, both WT and TLR2KO immune mice displayed similarly enhanced resistance to infection in comparison to their naïve counterparts. The frequencies ofM. tuberculosis-specific gamma interferon (IFN-γ)-producing T cells, the phenotypes of recruited T cells, and the granulomatous responses were also similar between WT and TLR2KO immune mice. Together, the findings from this study indicate that TLR2 signaling does not influence memory immunity toM. tuberculosis.

Role of Toll-like receptor 2 in the immune response against hepadnaviral infection

2012 ◽  
Vol 57 (3) ◽  
pp. 522-528 ◽  
Author(s):  
Xiaoyong Zhang ◽  
Zhiyong Ma ◽  
Hongyan Liu ◽  
Jia Liu ◽  
Zhongji Meng ◽  
...  
Keyword(s):  
Immune Response ◽  
Toll Like Receptor ◽  
Toll Like Receptor 2

scholarly journals Protective effect of Lactobacillus reuteri DSM 17938 against experimental necrotizing enterocolitis is mediated by Toll-like receptor 2

2018 ◽  
Vol 315 (2) ◽  
pp. G231-G240 ◽  
Author(s):  
Thomas K. Hoang ◽  
Baokun He ◽  
Ting Wang ◽  
Dat Q. Tran ◽  
J. Marc Rhoads ◽  
...  
Keyword(s):  
T Cells ◽  
Necrotizing Enterocolitis ◽  
Immune Modulation ◽  
Lactobacillus Reuteri ◽  
Inflammatory Responses ◽  
Cow Milk ◽  
Toll Like Receptor ◽  
Toll Like Receptor 2 ◽  
Anti Inflammatory

Lactobacillus reuteri DSM 17938 (LR 17938) has been shown to reduce the incidence and severity of necrotizing enterocolitis (NEC). It is unclear if preventing NEC by LR 17938 is mediated by Toll-like receptor 2 (TLR2), which is known to mediate proinflammatory responses to bacterial cell wall components. NEC was induced in newborn TLR2−/− or wild-type (WT) mice by the combination of gavage-feeding cow milk-based formula and exposure to hypoxia and cold stress. Treatment groups were administered formula supplemented with LR 17938 or placebo (deMan-Rogosa-Sharpe media). We observed that LR 17938 significantly reduced the incidence of NEC and reduced the percentage of activated effector CD4+T cells, while increasing Foxp3+ regulatory T cells in the intestinal mucosa of WT mice with NEC, but not in TLR2−/− mice. Dendritic cell (DC) activation by LR 17938 was mediated by TLR2. The percentage of tolerogenic DC in the intestine of WT mice was increased by LR 17938 treatment during NEC, a finding not observed in TLR2−/− mice. Furthermore, gut levels of proinflammatory cytokines IL-1β and IFN-γ were decreased after treatment with LR 17938 in WT mice but not in TLR2−/− mice. In conclusion, the combined in vivo and in vitro findings suggest that TLR2 receptors are involved in DC recognition and DC-priming of T cells to protect against NEC after oral administration of LR 17938. Our studies further clarify a major mechanism of probiotic LR 17938 action in preventing NEC by showing that neonatal immune modulation of LR 17938 is mediated by a mechanism requiring TLR2. NEW & NOTEWORTHY Lactobacillus reuteri DSM 17938 (LR 17938) has been shown to protect against necrotizing enterocolitis (NEC) in neonates and in neonatal animal models. The role of Toll-like receptor 2 (TLR2) as a sensor for gram-positive probiotics, activating downstream anti-inflammatory responses is unclear. Our current studies examined TLR2 −/− mice subjected to experimental NEC and demonstrated that the anti-inflammatory effects of LR 17938 are mediated via a mechanism requiring TLR2.

scholarly journals Interactions between Yersinia pestis V-antigen (LcrV) and human Toll-like receptor 2 (TLR2) in a modelled protein complex and potential mechanistic insights

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Tiandi Wei ◽  
Jing Gong ◽  
Guojing Qu ◽  
Mingyu Wang ◽  
Hai Xu
Keyword(s):  
Immune Response ◽  
Yersinia Pestis ◽  
Mechanistic Model ◽  
White Blood Cells ◽  
Dynamics Simulation ◽  
Structure Model ◽  
Toll Like Receptor ◽  
Toll Like Receptor 2 ◽  
V Antigen

Abstract Background Yersinia pestis, the etiological pathogen of plague, is capable of repressing the immune response of white blood cells to evade phagocytosis. The V-antigen (LcrV) was found to be involved in this process by binding to human Toll-like Receptor 2 (TLR2). The detailed mechanism behind this LcrV and TLR2 mediated immune response repression, however, is yet to be fully elucidated due to the lack of structural information. Results In this work, with protein structure modelling, we were able to construct a structure model of the heterotetramer of Y. pestis LcrV and human TLR2. Molecular dynamics simulation suggests the stability of this structure in aquatic environment. The LcrV model has a dumbbell-like structure with two globule domains (G1 at N-terminus and G2 away from membrane) connected with a coiled-coil linker (CCL) domain. The two horseshoe-shape TLR2 subunits form a V-shape structure, are not in direct contact with each other, and are held together by the LcrV homodimer. In this structure model, both the G1 and CCL domains are involved in the formation of LcrV homodimer, while all three domains are involved in LcrV-TLR2 binding. A mechanistic model was proposed based on this heterotetrameric structure model: The LcrV homodimer separates the TLR2 subunits to inhibit the dimerization of TLR2 and subsequent signal transfer for immune response; while LcrV could also inhibit the formation of heterodimers of TLR2 with other TLRs, and leads to immune response repression. Conclusions A heterotetrameric structure of Y. pestis LcrV and human TLR2 was modelled in this work. Analysis of this modelled structure showed its stability in aquatic environments and the role of LcrV domains and residues in protein-protein interaction. A mechanistic model for the role of LcrV in Y. pestis pathogenesis is raised based on this heterotetrameric structure model. This work provides a hypothesis of LcrV function, with which further experimental validation may elucidate the role of LcrV in human immune response repression.

scholarly journals Influenza virus-specific CD4+ T helper type 2 T lymphocytes do not promote recovery from experimental virus infection.

1994 ◽  
Vol 180 (4) ◽  
pp. 1273-1282 ◽  
Author(s):  
M B Graham ◽  
V L Braciale ◽  
T J Braciale
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Lymphocytes ◽  
Cd4 T Cells ◽  
Primary Role ◽  
T Helper ◽  
Helper Type

T lymphocytes play a primary role in recovery from viral infections and in antiviral immunity. Although viral-specific CD8+ and CD4+ T cells have been shown to be able to lyse virally infected targets in vitro and promote recovery from lethal infection in vivo, the role of CD4+ T lymphocytes and their mechanism(s) of action in viral immunity are not well understood. The ability to further dissect the role that CD4+ T cells play in the immune response to a number of pathogens has been greatly enhanced by evidence for more extensive heterogeneity among the CD4+ T lymphocytes. To further examine the role of CD4+ T cells in the immune response to influenza infection, we have generated influenza virus-specific CD4+ T cell clones from influenza-primed BALB/c mice with differential cytokine secretion profiles that are defined as T helper type 1 (Th1) clones by the production of interleukin 2 (IL-2) and interferon gamma (IFN-gamma), or as Th2 clones by the production of IL-4, IL-5, and IL-10. Our studies have revealed that Th1 clones are cytolytic in vitro and protective against lethal challenge with virus in vivo, whereas Th2 clones are noncytolytic and not protective. Upon further evaluation of these clonal populations we have shown that not only are the Th2 clones nonprotective, but that pulmonary pathology is exacerbated as compared with control mice as evidenced by delayed viral clearance and massive pulmonary eosinophilia. These data suggest that virus-specific CD4+ T cells of the Th2 subset may not play a primary role in virus clearance and recovery and may lead to immune mediated potentiation of injury.

scholarly journals Deficiency of CD73/ecto-5′-nucleotidase in mice enhances acute graft-versus-host disease

Blood ◽  
2012 ◽  
Vol 119 (19) ◽  
pp. 4554-4564 ◽  
Author(s):  
Hiroki Tsukamoto ◽  
Petya Chernogorova ◽  
Korcan Ayata ◽  
Ulrike V. Gerlach ◽  
Ankur Rughani ◽  
...  
Keyword(s):  
T Cells ◽  
Dominant Role ◽  
Extracellular Atp ◽  
Clinical Indication ◽  
A2a Receptor ◽  
Ifn Γ ◽  
Antigen Presenting ◽  
Adenosine A2a

Abstract Extracellular ATP and adenosine have immunoregulatory roles during inflammation. Elevated extracellular ATP is known to exacerbate GVHD, and the pharmacologic activation of the adenosine A2A receptor is protective. However, the role of endogenous adenosine is unknown. We used gene-targeted mice and a pharmacologic inhibitor to test the role of adenosine generated by CD73/ecto-5′-nucleotidase in GVHD. In allogeneic transplants, both donor and recipient CD73 were protective, with recipient CD73 playing the dominant role. CD73 deficiency led to enhanced T-cell expansion and IFN-γ and IL-6 production, and the migratory capacity of Cd73−/− T cells in vitro was increased. However, the number of regulatory T cells and expression of costimulatory molecules on antigen-presenting cells were unchanged. A2A receptor deficiency led to increased numbers of allogeneic T cells, suggesting that signaling through the A2A receptor via CD73-generated adenosine is a significant part of the mechanism by which CD73 limits the severity of GVHD. Pharmacologic blockade of CD73 also enhanced graft-versus-tumor activity. These data have clinical implications, as both the severity of GVHD and the strength of an alloimmune antitumor response could be manipulated by enhancing or blocking CD73 activity or adenosine receptor signaling depending on the clinical indication.

Shaping the CD4+ memory immune response against tuberculosis: the role of antigen persistence, location and multi-functionality

2012 ◽  
Vol 3 (1) ◽  
pp. 13-20 ◽  
Author(s):  
Lindsay Ancelet ◽  
Joanna Kirman
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Rational Design ◽  
Memory T Cells ◽  
T Cell Response ◽  
Intracellular Pathogens ◽  
Memory T Cell ◽  
Antigen Persistence ◽  
Memory Immune Response

AbstractEffective vaccination against intracellular pathogens, such as tuberculosis (TB), relies on the generation and maintenance of CD4 memory T cells. An incomplete understanding of the memory immune response has hindered the rational design of a new, more effective TB vaccine. This review discusses how the persistence of antigen, the location of memory cells, and their multifunctional ability shape the CD4 memory T cell response against TB.

scholarly journals Distinct Roles for MyD88 and Toll-Like Receptor 2 during Leishmania braziliensis Infection in Mice

2009 ◽  
Vol 77 (7) ◽  
pp. 2948-2956 ◽  
Author(s):  
Diego A. Vargas-Inchaustegui ◽  
Wendy Tai ◽  
Lijun Xin ◽  
Alison E. Hogg ◽  
David B. Corry ◽  
...  
Keyword(s):  
T Cells ◽  
Protective Immunity ◽  
Interleukin 12 ◽  
Leishmania Braziliensis ◽  
Toll Like Receptor ◽  
Enhanced Resistance ◽  
Toll Like Receptor 2 ◽  
Resistance To Infection

ABSTRACT We have previously reported that Leishmania braziliensis infection can activate murine dendritic cells (DCs) and upregulate signaling pathways that are essential for the initiation of innate immunity. However, it remains unclear whether Toll-like receptors (TLRs) are involved in L. braziliensis-mediated DC activation. To address this issue, we generated bone marrow-derived DCs from MyD88−/− and TLR2−/− mice and examined their responsiveness to parasite infection. While wild-type DCs were efficiently activated to produce cytokines and prime naïve CD4+ T cells, L. braziliensis-infected MyD88−/− DCs exhibited less activation and decreased production of interleukin-12 (IL-12) p40. Furthermore, MyD88−/− mice were more susceptible to infection in that they developed larger and prolonged lesions compared to those in control mice. In sharp contrast, the lack of TLR2 resulted in an enhanced DC activation and increased IL-12 p40 production after infection. As such, L. braziliensis-infected TLR2−/− DCs were more competent in priming naïve CD4+ T cells in vitro than were their controls, findings which correlated with an increased gamma interferon production in vivo and enhanced resistance to infection. Our results suggest that while MyD88 is indispensable for the generation of protective immunity to L. braziliensis, TLR2 seems to have a regulatory role during infection.

HEPATOCYTE TOLL-LIKE RECEPTOR 2 EXPRESSION IN VIVO AND IN VITRO: ROLE OF CYTOKINES IN INDUCTION OF RAT TLR2 GENE EXPRESSION BY LIPOPOLYSACCHARIDE

Shock ◽  
2000 ◽  
Vol 14 (3) ◽  
pp. 361-365 ◽  
Author(s):  
Shubing Liu ◽  
Neil A. Salyapongse ◽  
David A. Geller ◽  
Yoram Vodovotz ◽  
Timothy R. Billiar
Keyword(s):  
Gene Expression ◽  
Toll Like Receptor ◽  
Tlr2 Gene ◽  
Toll Like Receptor 2

Nitrosylation of Platelet MHC Class I Molecules Directs Their Movement into the Immunosuppressive MHC Class I Processing Pathway within Antigen Presenting Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 837-837
Author(s):  
John W. Semple ◽  
Edwin R. Speck ◽  
John Freedman
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Brefeldin A ◽  
Antigen Presenting Cells ◽  
Class I ◽  
Antigen Presenting ◽  
Platelet Transfusions

Abstract Previous studies have demonstrated that recipient mice require the production of nitric oxide (NO) within their antigen presenting cells (APC) in order to generate IgG anti-donor immunity against allogeneic platelet transfusions. NO has a complex biochemistry and several of its conjurors could be involved in this response; the most obvious is peroxynitrite (ONOO-) generated by the spontaneous combination of NO and superoxide (O2•−). ONOO- is a potent oxidant that can spontaneously nitrosylate lysine and tyrosine residues in proteins within the phagolysosome. To address the role of ONOO- in platelet immunity, we transfused GP91 PHOX knockout mice that lack the ability to produce O2•− and thus ONOO-. Results show that when wild type C57BL/6 mice were transfused with allogeneic BALB/c platelets, they developed a weak IgG anti-donor antibody response by the fifth transfusion. In contrast, PHOX KO mice generated IgG anti-donor antibodies by the 2nd transfusion and their IgG anti-donor antibody titres were significantly higher than the WT recipients. This suggested that ONOO- and protein nitrosylation may be linked with an immunosuppressive event within the recipient. This was confirmed by demonstrating that in vitro nitrosylation of platelet antigens with the ONOO- donor SIN-1 inhibited the ability of the platelets to mount an IgG immune response when transfused into allogeneic recipients. Nitrosylated platelet antigen trafficking within recipient APC was assessed by using adherent macrophages and various inhibitors of processing. When adherent APC were pulsed with nitrosylated platelet antigens in the presence of either Brefeldin A or proteosome inhibitors, IgG anti-platelet immunity against the platelets was restored. Furthermore, the IgG immunity could also be rescued against the nitrsosylated platelets if the recipients were first depleted of CD8+ T cells by injection of a monoclonal antibody. These results suggest that if platelet antigens are nitrosylated within antigen presenting cells, they are preferentially shunted to the MHC class I processing pathway and presented to CD8+ T cells that suppress the IgG immune response. Thus, it appears that reactive oxygen species act as intracellular regulators that determine whether a productive IgG immune response against platelet transfusions will occur.

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