scholarly journals Interleukin-21 Induces Short-Lived Effector CD8+ T Cells but Does Not Inhibit Their Exhaustion after Mycobacterium bovis BCG Infection in Mice

2018 ◽  
Vol 86 (8) ◽  
Author(s):  
Naoto Noguchi ◽  
Risa Nakamura ◽  
Shinya Hatano ◽  
Hisakata Yamada ◽  
Xun Sun ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Bovis ◽  
Cd8 T Cells ◽  
Absolute Number ◽  
Bacillus Calmette Guerin ◽  
Content Type ◽  
Effector Functions ◽  
Antigen 85B ◽  
Interleukin 21 ◽  
Recombinant Bcg

ABSTRACT Interleukin 21 (IL-21) is a pleiotropic common cytokine receptor γ chain cytokine that promotes the effector functions of NK cells and CD8+ T cells and inhibits CD8+ T cell exhaustion during chronic infection. We found that the absolute number of short-lived effector CD8+ T cells (SLECs) (KLRG1high CD127low) decreased significantly in IL-21 receptor-deficient (IL-21R−/−) mice during Mycobacterium bovis bacillus Calmette-Guérin (BCG) infection. Early effector CD8+ T cells (EECs) (KLRG1low CD127low) were normally generated in IL-21R−/− mice after infection. Exhausted CD8+ T cells (PD-1high KLRG1low) were also normally generated in IL-21R−/− mice after infection. Mixed bone marrow (BM) chimera and transfer experiments showed that IL-21R on CD8+ T cells was essential for the proliferation of EECs, allowing them to differentiate into SLECs after BCG infection. On the other hand, the number of SLECs increased significantly after infection with recombinant BCG (rBCG) that secreted an antigen 85B (Ag85B)–IL-21 fusion protein (rBCG–Ag85B–IL-21), but the number of exhausted CD8+ T cells did not change after rBCG–Ag85B–IL-21 infection. These results suggest that IL-21 signaling drives the differentiation of SLECs from EECs but does not inhibit the exhaustion of CD8+ T cells following BCG infection in mice.

scholarly journals Dendritic cells infected with Mycobacterium bovis bacillus Calmette Guerin activate CD8+ T cells with specificity for a novel mycobacterial epitope

2001 ◽  
Vol 13 (4) ◽  
pp. 451-458 ◽  
Author(s):  
Carl G. Feng ◽  
Caroline Demangel ◽  
Arun T. Kamath ◽  
Murdo Macdonald ◽  
Warwick J. Britton
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Mycobacterium Bovis ◽  
Cd8 T Cells ◽  
Bacillus Calmette Guerin

scholarly journals CD30 Is Required for Activation of a Unique Subset of Interleukin-17A-Producing γδ T Cells in Innate Immunity against Mycobacterium bovis Bacillus Calmette-Guérin Infection

2013 ◽  
Vol 81 (10) ◽  
pp. 3923-3934 ◽  
Author(s):  
Ying Guo ◽  
Xun Sun ◽  
Kensuke Shibata ◽  
Hisakata Yamada ◽  
Hiromi Muta ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Bovis ◽  
Early Stage ◽  
Γδ T Cells ◽  
Bacillus Calmette Guerin ◽  
Content Type ◽  
Interleukin 17A ◽  
Soluble Cd30 ◽  
Infection Inhibition

ABSTRACTInterleukin-17A (IL-17A)-producing γδ T cells are known to be activated followingMycobacterium bovisbacillus Calmette-Guérin (BCG) infection. Here, we show that CD30, a member of the tumor necrosis factor (TNF) receptor superfamily, is important for activation of IL-17A-producing γδ T cells after BCG infection. Vγ1−Vγ4−γδ T cells preferentially expressing Vγ6/Vδ1 genes were identified as the major source of IL-17A in the peritoneal cavity during the early stage of BCG infection. The number of IL-17A-producing Vγ1−Vγ4−γδ T cells bearing Vγ6 increased in peritoneal exudate cells (PEC) of wild-type (WT) mice but not in those of CD30 knockout (KO) mice in response to BCG infection. Consistently, CD30 ligand (CD30L) or CD30 expression, predominantly by Vγ1−Vγ4−γδ T cells, was rapidly upregulated after BCG infection. Inhibition of CD30L/CD30 signaling byin vivoadministration of a soluble CD30 and immunoglobulin fusion protein (CD30-Ig) severely impaired activation of IL-17A-producing Vγ1−Vγ4−γδ T cells in WT mice, while stimulating CD30L/CD30 signaling byin vivoadministration of agonistic anti-CD30 monoclonal antibody (MAb) restored IL-17A production by Vγ1−Vγ4−γδ T cells in CD30L KO mice after BCG infection. These results suggest that CD30 signaling plays an important role in the activation of IL-17A-producing Vγ1−Vγ4−γδ T cells bearing Vγ6 at an early stage of BCG infection.

scholarly journals Virally Activated CD8 T Cells Home to Mycobacterium bovis BCG-Induced Granulomas but Enhance Antimycobacterial Protection Only in Immunodeficient Mice

2006 ◽  
Vol 75 (3) ◽  
pp. 1154-1166 ◽  
Author(s):  
Laura H. Hogan ◽  
Dominic O. Co ◽  
Jozsef Karman ◽  
Erika Heninger ◽  
M. Suresh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mycobacterium Bovis ◽  
Cd8 T Cells ◽  
Bacterial Load ◽  
Granulomatous Inflammation ◽  
Cd8 T Cell ◽  
Activated T Cells ◽  
Immunodeficient Mice ◽  
Ifn Γ

ABSTRACT The effect of secondary infections on CD4 T-cell-regulated chronic granulomatous inflammation is not well understood. Here, we have investigated the effect of an acute viral infection on the cellular composition and bacterial protection in Mycobacterium bovis strain bacille Calmette-Guérin (BCG)-induced granulomas using an immunocompetent and a partially immunodeficient murine model. Acute lymphocytic choriomeningitis virus (LCMV) coinfection of C57BL/6 mice led to substantial accumulation of gamma interferon (IFN-γ)-producing LCMV-specific T cells in liver granulomas and increased local IFN-γ. Despite traffic of activated T cells that resulted in a CD8 T-cell-dominated granuloma, the BCG liver organ load was unaltered from control levels. In OT-1 T-cell-receptor (TCR) transgenic mice, ovalbumin (OVA) immunization or LCMV coinfection of BCG-infected mice induced CD8 T-cell-dominated granulomas containing large numbers of non-BCG-specific activated T cells. The higher baseline BCG organ load in this CD8 TCR transgenic animal allowed us to demonstrate that OVA immunization and LCMV coinfection increased anti-BCG protection. The bacterial load remained substantially higher than in mice with a more complete TCR repertoire. Overall, the present study suggests that peripherally activated CD8 T cells can be recruited to chronic inflammatory sites, but their contribution to protective immunity is limited to conditions of underlying immunodeficiency.

scholarly journals Altered effector functions of virus‐specific and virus cross‐reactive CD8 + T cells in mice immunized with related flaviviruses

2010 ◽  
Vol 40 (5) ◽  
pp. 1315-1327 ◽  
Author(s):  
Derek W. Trobaugh ◽  
Liyan Yang ◽  
Francis A. Ennis ◽  
Sharone Green
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Effector Functions

scholarly journals Activation Associated ERK1/2 Signaling Impairments in CD8+ T Cells Co-Localize with Blunted Polyclonal and HIV-1 Specific Effector Functions in Early Untreated HIV-1 Infection

PLoS ONE ◽  
2013 ◽  
Vol 8 (10) ◽  
pp. e77412 ◽  
Author(s):  
Timothy Q. Crawford ◽  
Fredrick M. Hecht ◽  
Christopher D. Pilcher ◽  
Lishomwa C. Ndhlovu ◽  
Jason D. Barbour
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Effector Functions ◽  
Specific Effector ◽  
Hiv 1

scholarly journals Evaluation of the Immunogenicity of Mycobacterium bovis BCG Delivered by Aerosol to the Lungs of Macaques

2015 ◽  
Vol 22 (9) ◽  
pp. 992-1003 ◽  
Author(s):  
A. D. White ◽  
C. Sarfas ◽  
K. West ◽  
L. S. Sibley ◽  
A. S. Wareham ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Mycobacterium Bovis ◽  
Cd8 T Cells ◽  
Bcg Vaccine ◽  
Effector Memory ◽  
Dependent Manner ◽  
Aerosol Delivery ◽  
Memory Phenotype ◽  
Bcg Vaccination

ABSTRACTNine million cases of tuberculosis (TB) were reported in 2013, with a further 1.5 million deaths attributed to the disease. When delivered as an intradermal (i.d.) injection, theMycobacterium bovisBCG vaccine provides limited protection, whereas aerosol delivery has been shown to enhance efficacy in experimental models. In this study, we used the rhesus macaque model to characterize the mucosal and systemic immune response induced by aerosol-delivered BCG vaccine. Aerosol delivery of BCG induced both Th1 and Th17 cytokine responses. Polyfunctional CD4 T cells were detected in bronchoalveolar lavage (BAL) fluid and peripheral blood mononuclear cells (PBMCs) 8 weeks following vaccination in a dose-dependent manner. A similar trend was seen in peripheral gamma interferon (IFN-γ) spot-forming units measured by enzyme-linked immunosorbent spot (ELISpot) assay and serum anti-purified protein derivative (PPD) IgG levels. CD8 T cells predominantly expressed cytokines individually, with pronounced tumor necrosis factor alpha (TNF-α) production by BAL fluid cells. T-cell memory phenotype analysis revealed that CD4 and CD8 populations isolated from BAL fluid samples were polarized toward an effector memory phenotype, whereas the frequencies of peripheral central memory T cells increased significantly and remained elevated following aerosol vaccination. Expression patterns of the α4β1 integrin lung homing markers remained consistently high on CD4 and CD8 T cells isolated from BAL fluid and varied on peripheral T cells. This characterization of aerosol BCG vaccination highlights features of the resulting mycobacterium-specific immune response that may contribute to the enhanced protection previously reported in aerosol BCG vaccination studies and will inform future studies involving vaccines delivered to the mucosal surfaces of the lung.

scholarly journals Stable Expression of Lentiviral Antigens by Quality-Controlled Recombinant Mycobacterium bovis BCG Vectors

2015 ◽  
Vol 22 (7) ◽  
pp. 726-741 ◽  
Author(s):  
Bryan E. Hart ◽  
Rose Asrican ◽  
So-Yon Lim ◽  
Jaimie D. Sixsmith ◽  
Regy Lukose ◽  
...  
Keyword(s):  
Mycobacterium Bovis ◽  
Antigen Expression ◽  
Full Length ◽  
Content Type ◽  
Immunodeficiency Virus ◽  
Vaccine Stability ◽  
Hiv Gp120 ◽  
Recombinant Bcg

ABSTRACTThe well-established safety profile of the tuberculosis vaccine strain,Mycobacterium bovisbacille Calmette-Guérin (BCG), makes it an attractive vehicle for heterologous expression of antigens from clinically relevant pathogens. However, successful generation of recombinant BCG strains possessing consistent insert expression has encountered challenges in stability. Here, we describe a method for the development of large recombinant BCG accession lots which stably express the lentiviral antigens, human immunodeficiency virus (HIV) gp120 and simian immunodeficiency virus (SIV) Gag, using selectable leucine auxotrophic complementation. Successful establishment of vaccine stability stems from stringent quality control criteria which not only screen for highly stable complemented BCG ΔleuCDtransformants but also thoroughly characterize postproduction quality. These parameters include consistent production of correctly sized antigen, retention of sequence-pure plasmid DNA, freeze-thaw recovery, enumeration of CFU, and assessment of cellular aggregates. Importantly, these quality assurance procedures were indicative of overall vaccine stability, were predictive for successful antigen expression in subsequent passaging bothin vitroandin vivo, and correlated with induction of immune responses in murine models. This study has yielded a quality-controlled BCG ΔleuCDvaccine expressing HIV gp120 that retained stable full-length expression after 1024-fold amplificationin vitroand following 60 days of growth in mice. A second vaccine lot expressed full-length SIV Gag for >1068-fold amplificationin vitroand induced potent antigen-specific T cell populations in vaccinated mice. Production of large, well-defined recombinant BCG ΔleuCDlots can allow confidence that vaccine materials for immunogenicity and protection studies are not negatively affected by instability or differences between freshly grown production batches.

scholarly journals CXCR6 regulates localization of tissue-resident memory CD8 T cells to the airways

2019 ◽  
Vol 216 (12) ◽  
pp. 2748-2762 ◽  
Author(s):  
Alexander N. Wein ◽  
Sean R. McMaster ◽  
Shiki Takamura ◽  
Paul R. Dunbar ◽  
Emily K. Cartwright ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Protective Immunity ◽  
Memory T Cells ◽  
Respiratory Pathogens ◽  
First Line ◽  
Memory Cd8 T Cells ◽  
Effector Functions ◽  
Signaling Axis ◽  
Resident Memory T Cells

Resident memory T cells (TRM cells) are an important first-line defense against respiratory pathogens, but the unique contributions of lung TRM cell populations to protective immunity and the factors that govern their localization to different compartments of the lung are not well understood. Here, we show that airway and interstitial TRM cells have distinct effector functions and that CXCR6 controls the partitioning of TRM cells within the lung by recruiting CD8 TRM cells to the airways. The absence of CXCR6 significantly decreases airway CD8 TRM cells due to altered trafficking of CXCR6−/− cells within the lung, and not decreased survival in the airways. CXCL16, the ligand for CXCR6, is localized primarily at the respiratory epithelium, and mice lacking CXCL16 also had decreased CD8 TRM cells in the airways. Finally, blocking CXCL16 inhibited the steady-state maintenance of airway TRM cells. Thus, the CXCR6/CXCL16 signaling axis controls the localization of TRM cells to different compartments of the lung and maintains airway TRM cells.

scholarly journals Impaired enolase 1 glycolytic activity restrains effector functions of tumor-infiltrating CD8+T cells

2019 ◽  
Vol 4 (31) ◽  
pp. eaap9520 ◽  
Author(s):  
Lelisa F. Gemta ◽  
Peter J. Siska ◽  
Marin E. Nelson ◽  
Xia Gao ◽  
Xiaojing Liu ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Biochemical Basis ◽  
Effector Functions ◽  
Glycolytic Activity ◽  
Functional Exhaustion ◽  
Critical Insight ◽  
Infiltrating Lymphocytes ◽  
Insight Into

In the context of solid tumors, there is a positive correlation between the accumulation of cytotoxic CD8+tumor-infiltrating lymphocytes (TILs) and favorable clinical outcomes. However, CD8+TILs often exhibit a state of functional exhaustion, limiting their activity, and the underlying molecular basis of this dysfunction is not fully understood. Here, we show that TILs found in human and murine CD8+melanomas are metabolically compromised with deficits in both glycolytic and oxidative metabolism. Although several studies have shown that tumors can outcompete T cells for glucose, thus limiting T cell metabolic activity, we report that a down-regulation in the activity of ENOLASE 1, a critical enzyme in the glycolytic pathway, represses glycolytic activity in CD8+TILs. Provision of pyruvate, a downstream product of ENOLASE 1, bypasses this inactivity and promotes both glycolysis and oxidative phosphorylation, resulting in improved effector function of CD8+TILs. We found high expression of both enolase 1 mRNA and protein in CD8+TILs, indicating that the enzymatic activity of ENOLASE 1 is regulated posttranslationally. These studies provide a critical insight into the biochemical basis of CD8+TIL dysfunction.

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