Poor correlation between BCG vaccination-induced T cell responses and protection against tuberculosis

Mittrücker, Hans‐Willi; Steinhoff, Ulrich; Köhler, Anne; Krause, M; Lazar, Doris; Mex, Peggy; Miekley, Delia; Kaufmann, Stefan H. E.

doi:10.1073/pnas.0703510104

Cited by 262 publications

(223 citation statements)

References 35 publications

(48 reference statements)

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“…However, expression of the gene encoding CD8 increased in a virulence-specific manner, an observation which has been linked to increased bacterial burden [22]. Among the cathepsin-encoding genes detected in our study, CATG, CATC and CATW transcript levels were elevated in H37Rv-infected iNOS -/-lungs at d30 p.i.…”

Section: Adaptive Immune Responsementioning

confidence: 64%

Combination of host susceptibility and Mycobacterium tuberculosis virulence define gene expression profile in the host

Beisiegel¹,

Mollenkopf²,

Hahnke³

et al. 2009

Eur J Immunol

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Progression and outcome of tuberculosis is governed by extensive crosstalk between pathogen and host. Analyses of global changes in gene expression during immune response to infection with Mycobacterium tuberculosis (M.tb) can help identify molecular markers of disease state and progression. Global distribution of M.tb strains with different degrees of virulence and drug resistance, especially for the immunocompromised host, make closer analyses of host responses more pressing than ever. Here, we describe global transcriptional responses of inducible nitric oxide synthase-deficient (iNOS -/-) and WT mice infected with two related M.tb strains of markedly different virulence, namely the M.tb laboratory strains H37Rv and H37Ra. Both hosts exhibited highly similar resistance to infection with H37Ra. In contrast, iNOS -/-mice rapidly succumbed to H37Rv, whereas WT mice developed chronic course of disease. By differential analyses, virulence-specific changes in global host gene expression were analyzed to identify molecular markers characteristic for chronic versus acute infection. We identified several markers unique for different stages of disease progression and not previously associated with virulencespecific host responses in tuberculosis.

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Section: Adaptive Immune Responsementioning

confidence: 64%

Combination of host susceptibility and Mycobacterium tuberculosis virulence define gene expression profile in the host

Beisiegel¹,

Mollenkopf²,

Hahnke³

et al. 2009

Eur J Immunol

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“…On day 5 p.i., WT or Irf4 −/− OT-I CD8 + T cells were recovered from spleens of recipient mice by MACS purification and equalized numbers of cells (1 × 10 6 ) were transferred into naive mice. One day later, target and control cells were prepared by loading of spleen cells with 10 −6 M of the peptides OVA 257-264 (target cells) or LCMV gp [33][34][35][36][37][38][39][40][41] (control cells), which were then stained with 2 μM or 0.2 μM CFSE, respectively. Target and control cells were then mixed in a 1:1 ratio and a total of 6 × 10 6 cells were injected into the recipients of activated OT-I cells.…”

Section: Discussionmentioning

confidence: 99%

The transcription factor Interferon Regulatory Factor 4 is required for the generation of protective effector CD8 ⁺ T cells

Raczkowski

Ritter

Heesch

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Robust cytotoxic CD8 + T-cell response is important for immunity to intracellular pathogens. Here, we show that the transcription factor IFN Regulatory Factor 4 (IRF4) is crucial for the protective CD8 + T-cell response to the intracellular bacterium Listeria monocytogenes. IRF4-deficient (Irf4 −/− ) mice could not clear L. monocytogenes infection and generated decreased numbers of L. monocytogenesspecific CD8 + T cells with impaired effector phenotype and function. Transfer of wild-type CD8 + T cells into Irf4 −/− mice improved bacterial clearance, suggesting an intrinsic defect of CD8 + T cells in Irf4 −/− mice. Following transfer into wild-type recipients, Irf4 −/− CD8 + T cells became activated and showed initial proliferation upon L. monocytogenes infection. However, these cells could not sustain proliferation, produced reduced amounts of IFN-γ and TNF-α, and failed to acquire cytotoxic function. Forced IRF4 expression in Irf4 −/− CD8 + T cells rescued the defect. During acute infection, Irf4 −/− CD8 + T cells demonstrated diminished expression of B lymphocyte-induced maturation protein-1 (Blimp-1), inhibitor of DNA binding (Id)2, and T-box expressed in T cells (T-bet), transcription factors programming effector-cell generation. IRF4 was essential for expression of Blimp-1, suggesting that altered regulation of Blimp-1 contributes to the defects of Irf4 −/− CD8 + T cells. Despite increased levels of B-cell lymphoma 6 (BCL-6), Eomesodermin, and Id3, Irf4 −/− CD8 + T cells showed impaired memory-cell formation, indicating additional functions for IRF4 in this process. As IRF4 governs B-cell and CD4 + T-cell differentiation, the identification of its decisive role in peripheral CD8 + T-cell differentiation, suggests a common regulatory function for IRF4 in adaptive lymphocytes fate decision.

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“…In vitro re-stimulation of cells and flow cytometric determination of cytokine expression T-cell responses in lung and spleen were determined by intracellular IFN-g staining [44]. Cells (1-3 Â 10 6 ) were cultured in a volume of 1 mL complete RPMI medium and stimulated for 5 h with a combination of the peptides Ag85A 241-260 (QDAYNAGGGH NGVFDFPDSG) and Ag85B 240-260 (FQDAYNAAGG HNAVFNFPPN G) both at 10 mM or with 1 mM of the peptide Mtb32/RV0125 309-318 (GAPINSATAM) [45,46].…”

Section: Purification Of Cells From Different Tissuesmentioning

confidence: 99%

A role for IL‐18 in protective immunity against Mycobacterium tuberculosis

et al. 2010

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Tuberculosis remains the most hazardous bacterial infection worldwide. The causative agent, Mycobacterium tuberculosis, is a facultative intracellular pathogen of resting MU. IFN-c secreted by natural killer, CD4 Th 1 and CD8 T cells upon instruction by IL-12 and -18 activates MU to restrict mycobacterial growth. Production of both cytokines is induced by TLR signalling in DC and MU. Mice deficient for the TLR adaptor, MyD88, are highly susceptible to M. tuberculosis infection. Shared usage of MyD88 by signalling cascades for TLR and receptors for IL-1 and IL-18 prompted us to revisit the role of IL-18 during experimental infection with M. tuberculosis. We show that mice deficient for IL-18 and MyD88 but not for IL-18 receptor promptly succumbed to M. tuberculosis infection in contrast to WT or TLR-2/-4 double KO mice indicating that lack of IL-18 contributes to the high susceptibility of MyD88 KO mice to M. tuberculosis. Without IL-18, the protective Th1 response was decreased and hence, mycobacterial propagation was favoured. Neutrophildriven lung immunopathology concomitant with unrestrained growth of tubercle bacilli are most likely responsible for the premature death of IL-18 KO mice. Thus, IL-18 plays a decisive role in protective immunity against tuberculosis.Key words: IFN-c . IL-18 . Mouse . Neutrophils . Tuberculosis IntroductionDespite more than 125 years of research and development, tuberculosis (TB) remains the most hazardous bacterial infection worldwide with approximately 2 million people dying of the disease annually [1]. The risk of disease is increased by immunocompromising conditions such as AIDS emphasizing that T-cell immunity protects latently infected individuals against active TB. The innate immune response to Mycobacterium tuberculosis instructs acquired immunity in the initial stage, and executes effector mechanisms in the chronic stage.M. tuberculosis is usually transmitted via aerosols and establishes stable infection in the lung. There, M. tuberculosis is engulfed by MF and DC, which serve as host cells for mycobacterial survival and propagation. Binding of mycobacterial ligands to TLR-2, -4 and -9 promotes release of chemokines and proinflammatory cytokines, expression of adhesion molecules and attraction of MF, DC and PMN. Two crucial MF-and DCderived cytokines, , induce NK-cell activity and bias immunity towards a Th1 cell response characterized by profound 396IFN-g production, which is considered critical for protection against M. tuberculosis [2]. Activated MF express anti-mycobacterial molecules such as nitric oxide synthase (NOS)-2 (also known as inducible NOS) and LRG47 as well as cytokines such as TNF-a, which promotes granuloma formation within the infected tissue to sequester the bacilli from dissemination [2].Despite the prevailing assumption that resistance to M. tuberculosis infection depends on microbe sensing through TLR, their importance for mounting a protective immune response against M. tuberculosis remains controversial. While some groups found that TLR-mediated...

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Poor correlation between BCG vaccination-induced T cell responses and protection against tuberculosis

Cited by 262 publications

References 35 publications

Combination of host susceptibility and Mycobacterium tuberculosis virulence define gene expression profile in the host

Combination of host susceptibility and Mycobacterium tuberculosis virulence define gene expression profile in the host

The transcription factor Interferon Regulatory Factor 4 is required for the generation of protective effector CD8 ⁺ T cells

A role for IL‐18 in protective immunity against Mycobacterium tuberculosis

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Poor correlation between BCG vaccination-induced T cell responses and protection against tuberculosis

Cited by 262 publications

References 35 publications

Combination of host susceptibility and Mycobacterium tuberculosis virulence define gene expression profile in the host

Combination of host susceptibility and Mycobacterium tuberculosis virulence define gene expression profile in the host

The transcription factor Interferon Regulatory Factor 4 is required for the generation of protective effector CD8 + T cells

A role for IL‐18 in protective immunity against Mycobacterium tuberculosis

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The transcription factor Interferon Regulatory Factor 4 is required for the generation of protective effector CD8 ⁺ T cells