Interleukin-7 or Interleukin-15 Enhances Survival of<i>Mycobacterium tuberculosis</i>-Infected Mice

Maeurer, Markus; Trinder, P. K. E.; Hommel, Gerhard; Walter, Wolfgang; Freitag, Kirsten; Atkins, Derek; Störkel, Stefan

doi:10.1128/iai.68.5.2962-2970.2000

Cited by 87 publications

(64 citation statements)

References 43 publications

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“…In accordance with the importance of CD8 + T cells for protection against a number of pathogens, IL-15 was shown to improve the proliferation of memory/effector CD8 + T cells and protective CD8 + T cell-mediated immune responses such as IFN-c production and cytotoxicity [37][38][39] With respect to mycobacterial infections, there are discrepant reports on the role of IL-15. Following infection with M. bovis BCG or Mtb H37Rv, treatment of infected mice with recombinant IL-15 or overexpression of IL-15 resulted in enhanced anti-mycobacterial protection which was attributed to the ability of this cytokine to promote NK and CD8 + T cell-mediated immune responses [23][24][25]. In contrast, a more recent report showed that administration of exogenous IL-15 did not influence the course of Mtb infection in wildtype mice, and that Mtb-infected IL-15 -/-mice had only mild defects in protective CD8 + T cell-mediated immune responses [45].…”

Section: Discussionmentioning

confidence: 99%

“…Following infection with M. bovis BCG or Mtb H37Rv, treatment of infected mice with recombinant IL-15 or overexpression of IL-15 resulted in enhanced anti-mycobacterial protection which was attributed to the ability of this cytokine to promote NK and CD8 + T cell-mediated immune responses [23][24][25]. In contrast, a more recent report showed that administration of exogenous IL-15 did not influence the course of Mtb infection in wildtype mice, and that Mtb-infected IL-15 -/-mice had only mild defects in protective CD8 + T cell-mediated immune responses [45].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, mice lacking IL-15 or IL-15Ra are deficient in the generation of memory-phenotype CD8 + T cells [18,19] and are highly susceptible to infection with viruses [20,21]. Treatment with exogenous IL-15 or overexpression of endogenous IL-15 results in enhanced protection against mycobacterial infections [22][23][24][25]. However, the mechanisms by which IL-15 mediates protection during experimental TB are not completely understood.…”

Section: Introductionmentioning

confidence: 99%

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Interleukin‐15 mediates protection against experimental tuberculosis: A role for NKG2D‐dependent effector mechanisms of CD8⁺ T cells

et al. 2006

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CD8 + T cells are involved in protection againstMycobacterium tuberculosis infection and represent a promising target for new vaccine strategies. Because IL-15 is important for the homeostasis of CD8 + T cells, we studied the immune response in IL-15-deficient mice during tuberculosis. In the absence of IL-15, CD8 + T cells failed to efficiently accumulate in draining lymph nodes and at the site of infection. The expression of antigen-specific effector functions, such as the production of interferon-c and cytotoxicity, were impaired in CD8 + T cells, but not CD4 + T cells, from IL-15-deficient mice. This defect was associated with an increased mortality of IL-15-deficient mice during the chronic phase of infection. The lectin-like stimulatory receptor natural killer group 2D (NKG2D) was up-regulated on CD8 + T cells only from wild-type mice, but not from IL-15-deficient mice. Mechanistically, blocking NKG2D function with an mAb inhibited M. tuberculosis-directed CD8 + T cell responses in vitro. We conclude that in addition to regulating the expansion of CD8 + T cells, IL-15 is also necessary for inducing effector mechanisms in CD8 + T cells that depend on NKG2D expression. Hence, our results implicate IL-15 and NKG2D as promising targets for modulating CD8 + T cellmediated protection against tuberculosis. IntroductionHuman tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is responsible for eight million new cases and two million deaths annually [1]. Improved vaccination strategies will need to target all mechanisms that contribute to restricting the growth of Mtb [2]. Although the cell-mediated immune response is known to be critical in host defense against infection with mycobacteria, the relative contribution of T cell subsets and the mechanisms by which T cells participate in the control of infection are still not completely defined. It is generally accepted that both, CD4 + and CD8 + T cells, are an essential component of protective immunity against TB [3]. CD4 + T cells are particularly critical during the early phase of infection, while CD8 + T cells appear to contribute mostly at later stages [4,5]. Both, CD4 + and CD8 + T cells, produce interferon-c (IFN-c) which in turn stimulates the anti-microbial activity of macrophages. Intracellular pathogens are then killed through reactive nitrogen intermediates produced by the inducible nitric oxide synthase [6] or through effector mechanisms mediated by the newly described member of the 47-kD guanosine triphosphatase family, . CD8 + T cells can also cause death of both target cells and their intracellular bacterial cargo, either through perforin-dependent cytolysis by the release of granzymes and granulysin, or by ligation of Fas ligand (FasL) on their surface with Fas on infected macrophages [5,[8][9][10]. Because CD8 + T cells are involved in protection during the chronic stage of TB [4,5,11], and participate in memory immune responses to Mtb infection [12], generating a more robust CD8 + T cell response may provide an effective vaccination strate...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Interleukin‐15 mediates protection against experimental tuberculosis: A role for NKG2D‐dependent effector mechanisms of CD8⁺ T cells

et al. 2006

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“…Furthermore, IL-15 regulates the expression of CXCR3, one of the genes overexpressed in sarcoidosis lung tissues (see Figure 1), in T cells derived from the lungs of patients with sarcoidosis (29). Unlike IL-15, increased expression of IL-7 has not been previously described in sarcoidosis; however, IL-7 protein is shown to be essential for the expansion of T-cell populations (25) and is expressed in the stroma surrounding infectious granulomas (30), where it is thought to promote the clearance of intracellular pathogens (31). A recent investigation indicates that IL-7 is essential for CD4 1 T-cell responses to viral infection and that IL-15 plays an accessory role in this process (32).…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling Identifies MMP-12 and ADAMDEC1 as Potential Pathogenic Mediators of Pulmonary Sarcoidosis

Crouser¹,

Culver²,

Knox³

et al. 2009

Am J Respir Crit Care Med

135

126

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“…The CD4 + , CD8-depleted PBMC population was incubated with the respective PE-labelled tetramer reagents (1 lg of tetramer/2 · 10 7 cells) for 2 h, washed once, and incubated for 15 min with an anti-PE-directed MoAb attached to immunomagnetic beads (Miltenyi, Bergisch Gladbach, Germany) as previously described [11]. Tetramer-sorted cells were exposed to autologous macrophages which had been infected either with M. tuberculosis or with Mycobacterium avium intracellulare as described in detail [19] for 72 h. The anti-DR-specific MoAb L243 was used to block MHC class II-restricted T-cell recognition of naturally processed and presented antigens, while the anti-MHC class I-specific MoAb w6/32 was used as a negative control. Supernatants were harvested and tested for IFN-c or GM-CSF using the ELISA system obtained from Diaclone, Besancon, France.…”

Section: Methodsmentioning

confidence: 99%

MHC class II Tetramer Guided Detection of Mycobacterium tuberculosis‐specific CD4⁺ T Cells in Peripheral Blood from Patients with Pulmonary Tuberculosis

Höhn¹,

Kortsik²,

Zehbe³

et al. 2007

Scand J Immunol

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Novel diagnostic tools are needed to diagnose latent infection and to provide biologically meaningful surrogate markers to define cellular immune responses against Mycobacterium tuberculosis (MTB). Interferon gamma‐based assays have recently been developed in addition to the more than 100‐year‐old tuberculin skin test (TST) for the immune diagnosis of MTB in blood. The advent of soluble MHC/peptide tetramer molecules allows to objectively enumerate antigen‐specific T cells. We identified novel MHC class II‐restricted MTB epitopes and used HLA‐DR4 tetrameric complexes to visualize ex vivo CD4+ T cells directed against the antigens Ag85B and the 19‐kDa lipoprotein, shared between MTB and other Mycobacterium species, and CD4+ T cells which recognize the MTB‐associated ESAT‐6 antigen. MTB‐reactive CD4+ T cells reside predominantly in the CD45RA+ CD28+ and CD45− CD28+ T‐cell subset and recognize naturally processed and presented MTB epitopes. HLA‐DR4‐restricted, Ag85B or ESAT‐6‐specific CD4+ T cells show similar dynamics over time in peripheral blood mononuclear cells (PBMC) when compared with CD8+ T cells directed against the corresponding HLA‐A2‐presented MTB epitopes in patients with pulmonary MTB infection and subsequent successful therapy. This was not found to be true for T‐cell responses directed against the 19‐kDa lipoprotein. The dissection of the cellular immune response in M. tuberculosis infection will enable novel strategies for monitoring MTB vaccine candidates and to gauge CD4+ T cells directed against MTB.

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Interleukin-7 or Interleukin-15 Enhances Survival ofMycobacterium tuberculosis-Infected Mice

Cited by 87 publications

References 43 publications

Interleukin‐15 mediates protection against experimental tuberculosis: A role for NKG2D‐dependent effector mechanisms of CD8⁺ T cells

Interleukin‐15 mediates protection against experimental tuberculosis: A role for NKG2D‐dependent effector mechanisms of CD8⁺ T cells

Gene Expression Profiling Identifies MMP-12 and ADAMDEC1 as Potential Pathogenic Mediators of Pulmonary Sarcoidosis

MHC class II Tetramer Guided Detection of Mycobacterium tuberculosis‐specific CD4⁺ T Cells in Peripheral Blood from Patients with Pulmonary Tuberculosis

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Interleukin-7 or Interleukin-15 Enhances Survival ofMycobacterium tuberculosis-Infected Mice

Cited by 87 publications

References 43 publications

Interleukin‐15 mediates protection against experimental tuberculosis: A role for NKG2D‐dependent effector mechanisms of CD8+ T cells

Interleukin‐15 mediates protection against experimental tuberculosis: A role for NKG2D‐dependent effector mechanisms of CD8+ T cells

Gene Expression Profiling Identifies MMP-12 and ADAMDEC1 as Potential Pathogenic Mediators of Pulmonary Sarcoidosis

MHC class II Tetramer Guided Detection of Mycobacterium tuberculosis‐specific CD4+ T Cells in Peripheral Blood from Patients with Pulmonary Tuberculosis

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Interleukin‐15 mediates protection against experimental tuberculosis: A role for NKG2D‐dependent effector mechanisms of CD8⁺ T cells

Interleukin‐15 mediates protection against experimental tuberculosis: A role for NKG2D‐dependent effector mechanisms of CD8⁺ T cells

MHC class II Tetramer Guided Detection of Mycobacterium tuberculosis‐specific CD4⁺ T Cells in Peripheral Blood from Patients with Pulmonary Tuberculosis