Depletion of NK cells results in disseminating lethal infection with <i>Bordetella pertussis</i> associated with a reduction of antigen‐specific Th1 and enhancement of Th2, but not Tr1 cells

Byrne, Patricia; McGuirk, Peter; Todryk, Stephen; Mills, Kingston H. G.

doi:10.1002/eji.200425092

Cited by 125 publications

(109 citation statements)

References 25 publications

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“…Clearance of B. pertussis from the respiratory tract is mediated by IFN-g secreted by Th1 and NK cells, as well as Ag-specific Ab production (4,8). Furthermore, we demonstrated that adaptive immunity induced by vaccination was dependent on Ag-specific IL-17 production (5).…”

Section: Resultsmentioning

confidence: 99%

“…Adaptive immunity generated by previous infection or immunization with the whole-cell vaccine is effective at preventing severe disease, and studies in a mouse model suggested that a combination of Abs and Th1 and Th17 cells are involved (3)(4)(5)(6)(7). Protection against a primary infection with B. pertussis is mediated by innate and adaptive immune responses, and IFN-g secreted by NK and Th1 cells seems to be critical (4,8,9). However, host immune responses are suppressed, especially early in infection, because of the induction of regulatory T cells (10), as well as by the various immune-subversion strategies evolved by B. pertussis virulence factors to prolong survival in the host (2,11,12).…”

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confidence: 99%

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Inflammasome Activation by Adenylate Cyclase Toxin Directs Th17 Responses and Protection against Bordetella pertussis

Dunne

Ross

Pospíšilová

et al. 2010

The Journal of Immunology

158

161

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Inflammasome-mediated IL-1β production is central to the innate immune defects that give rise to certain autoinflammatory diseases and may also be associated with the generation of IL-17–producing CD4+ T (Th17) cells that mediate autoimmunity. However, the role of the inflammasome in driving adaptive immunity to infection has not been addressed. In this article, we demonstrate that inflammasome-mediated IL-1β plays a critical role in promoting Ag-specific Th17 cells and in generating protective immunity against Bordetella pertussis infection. Using a murine respiratory challenge model, we demonstrated that the course of B. pertussis infection was significantly exacerbated in IL-1R type I-defective (IL-1RI−/−) mice. We found that adenylate cyclase toxin (CyaA), a key virulence factor secreted by B. pertussis, induced robust IL-1β production by dendritic cells through activation of caspase-1 and the NALP3-containing inflammasome complex. Using mutant toxins, we demonstrate that CyaA-mediated activation of caspase-1 was not dependent on adenylate cyclase enzyme activity but was dependent on the pore-forming capacity of CyaA. In addition, CyaA promoted the induction of Ag-specific Th17 cells in wild-type but not IL-1RI−/− mice. Furthermore, the bacterial load was enhanced in IL-17–defective mice. Our findings demonstrate that CyaA, a virulence factor from B. pertussis, promotes innate IL-1β production via activation of the NALP3 inflammasome and, thereby, polarizes T cell responses toward the Th17 subtype. In addition to its known role in subverting host immunity, our findings suggest that CyaA can promote IL-1β–mediated Th17 cells, which promote clearance of the bacteria from the respiratory tract.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Inflammasome Activation by Adenylate Cyclase Toxin Directs Th17 Responses and Protection against Bordetella pertussis

Dunne

Ross

Pospíšilová

et al. 2010

The Journal of Immunology

158

161

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“…Anti-ASGM1 Ab has been used to deplete NK cells in mice (34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44). However, it has been known for some time that ASGM1 can be upregulated on leukocytes other than NK cells in the context of viral infection (45).…”

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confidence: 99%

Differential Regulation of GM1 and Asialo-GM1 Expression by T Cells and Natural Killer (NK) Cells in Respiratory Syncytial Virus Infection

et al. 2008

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We previously reported that respiratory syncytial virus (RSV) infection increases lung CD8 ϩ T cell GM1 expression. The related lipid asialo-GM1 (ASGM1) is expressed by T cells in viral infection and by natural killer (NK) cells. The in vivo co-expression of GM1 and ASGM1 by immune cells is not defined. Here we analyzed lung lymphocyte GM1 and ASGM1 expression in RSV-infected mice. GM1 and ASGM1 were coordinately upregulated by activated CD8 ϩ T cells in RSV-infected BALB/c and C57BL/6 mice. In contrast, RSV infection had no effect on constitutively high NK cell GM1 expression, while increasing NK cell ASGM1 expression. GM1 and ASGM1 co-localized in lipid raft structures in NK and CD8 ϩ T cells sorted from the lungs of RSV-infected mice. Anti-ASGM1 Ab treatment of RSV-infected BALB/c mice depleted GM1/ASGM1-expressing NK cells and GM1/ASGM1-expressing T cells, reduced lung IFN-␥ levels, increased viral load, delayed viral clearance, and reduced illness. STAT1 Ϫ/Ϫ mice are more susceptible to RSV replication and disease than wild-type mice. In RSV-infected STAT1 Ϫ/Ϫ mice, anti-ASGM1 Ab altered cytokine levels, but in contrast to BALB/c mice, antibody treatment had no effect on viral load or illness. Taken together, GM1 and ASGM1 expression are differentially regulated by T and NK cells in RSV infection. Also, GM1/ASGM1-expressing cells are important for control of RSV in BALB/c mice, whereas STAT1 Ϫ/Ϫ mice clear RSV by an alternative pathway. 327

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“…Indeed, the in vivo default mechanism of CD4 ϩ T cells in the absence of NK cells appears to be strongly biased toward the acquisition of a Th2 phenotype. 49,50 In humans, direct evidence for the close contact between NK cells and MDDCs as well as for the ability of NK cells to kill iMDDCs after migration to peripheral tissues has been provided in atopic skin lesions induced by the Malassezia yeast. 51 Finally, it is of note that the encounter between NK cells and different DC subtypes is not limited only to pathogen-invaded peripheral tissues but occurs also in secondary lymphoid compartments.…”

Section: Discussionmentioning

confidence: 99%

Multidirectional interactions are bridging human NK cells with plasmacytoid and monocyte-derived dendritic cells during innate immune responses

Chiesa

Romagnani

Thiel

et al. 2006

Blood

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During innate immune responses, natural killer (NK) cells may interact with both plasmacytoid dendritic cells (pDCs) and monocyte-derived dendritic cells (MDDCs). We show that freshly isolated NK cells promote the release by pDCs of IFN-␣, in a CpG-dependent manner, whereas they induce IL-6 production in a CpG-independent manner. In turn pDCderived IFN-␣ up-regulates NK-mediated killing, whereas IL-6 could promote B-cell differentiation. We also show that expo- IntroductionInnate immune responses play a crucial role not only in controlling pathogen invasion, but also in instructing the adaptive immune system to initiate a specific response against infecting pathogens. 1 Natural killer (NK) cells and dendritic cells (DCs) represent crucial effector cells of the innate immune system. 2,3 Several reports have highlighted the importance of the reciprocal interaction between NK cells and DCs during the early stages of innate immune responses. [4][5][6][7][8][9] The NK/DC cross talk can occur within inflamed peripheral tissues and results in a potent DC-induced activation of NK-cell functions, which, in turn, exert a modulatory role on DC activity. Pathogen clearance mediated by innate effector mechanisms is, at least in part, the result of the DC-induced up-regulation of NK-cell cytotoxicity and of the release of antimicrobial cytokines from various cell types recruited at the inflammatory sites. 10,11 The reciprocal interactions between NK and DCs could regulate the quality of DCs undergoing maturation. For example, because NK cells are capable of killing immature DC (iDCs), the existence of an "editing" process has been suggested, by which DCs may or may not acquire the ability to prime Th1 immune responses. 12,13 Most reports regarding the cross talk between NK cells and DCs in humans have been focused on the interactions with monocyte-derived dendritic cells (MDDCs), whereas only limited information exists on the interaction with plasmacytoid DCs (pDCs). 14,15 pDCs are capable of producing large amounts of IFN-␣ in response to viral DNA or RNA. 16 This suggests that, together with NK cells, they play an important role in sensing viral infections and in promoting antiviral innate responses. We have previously shown that pDCs, on stimulation through TLR9, can activate NK cells to kill various types of tumor cells. Moreover, following TLR9 engagement, pDCs could induce a selective proliferation of the small NK-cell subset characterized by the CD56 bright phenotype. 15 In addition, IL-2-activated NK cells have been shown to promote pDC maturation and IFN-␣ release. 14 On the other hand, it is not clear whether, in humans, this event can actually occur during the early phases of innate immune responses in which T cells (ie, the only IL-2-producing cells) are not involved.In the present study we show that the regulatory effect of NK cells on pDC function does not strictly require exposure to IL-2, because also freshly isolated NK cells promoted pDC maturation and cytokine release. Moreover, an abundant IFN-␣ release b...

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Depletion of NK cells results in disseminating lethal infection with Bordetella pertussis associated with a reduction of antigen‐specific Th1 and enhancement of Th2, but not Tr1 cells

Cited by 125 publications

References 25 publications

Inflammasome Activation by Adenylate Cyclase Toxin Directs Th17 Responses and Protection against Bordetella pertussis

Inflammasome Activation by Adenylate Cyclase Toxin Directs Th17 Responses and Protection against Bordetella pertussis

Differential Regulation of GM1 and Asialo-GM1 Expression by T Cells and Natural Killer (NK) Cells in Respiratory Syncytial Virus Infection

Multidirectional interactions are bridging human NK cells with plasmacytoid and monocyte-derived dendritic cells during innate immune responses

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