Cutting Edge: Activation by Innate Cytokines or Microbial Antigens Can Cause Arrest of Natural Killer T Cell Patrolling of Liver Sinusoids

Velázquez, Peter; Cameron, Thomas O.; Kinjo, Yuki; Nagarajan, Niranjana; Kronenberg, Mitchell; Dustin, Michael L.

doi:10.4049/jimmunol.180.4.2024

Cited by 77 publications

(73 citation statements)

References 15 publications

(21 reference statements)

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“…48 Interestingly, NKT cells patrolling liver sinusoids also underwent migration arrest on addition of IL-12 and IL-18, similar to the effect observed from addition of a microbial glycolipid antigen. 49 The induction of cytoplasmic calcium flux is thought to be required for T-cell migration arrest; however, although we detected calcium flux in response to a microbial antigen, in our system human NKT cells showed no flux in response to IL-12 and IL-18. Hence, it is possible that certain physiologic APCs, perhaps including those present in liver sinusoids, are better able to induce NKT cell calcium flux than the cells used in our experiments.…”

contrasting

confidence: 53%

“…Hence, it is possible that certain physiologic APCs, perhaps including those present in liver sinusoids, are better able to induce NKT cell calcium flux than the cells used in our experiments. However, as the migration arrest observed in vivo after addition of IL-12 and IL-18 appeared only partially dependent on recognition of CD1d, 49 it is also possible that these cytokines can cause arrest by a different mechanism, such as modulation of the expression levels of adhesion ligands.…”

Section: Discussionmentioning

confidence: 99%

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Natural killer T-cell autoreactivity leads to a specialized activation state

Wang¹,

Chen²,

Rodenkirch

et al. 2008

Blood

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Natural killer T (NKT) cells are innate-likeT cells that recognize specific microbial antigens and also display autoreactivity to self-antigens. The nature of NKT-cell autoreactive activation remains poorly understood. We show here that the mitogenactivated protein kinase (MAPK) pathway is operative during human NKT-cell autoreactive activation, but calcium signaling is severely impaired. This results in a response that is biased toward granulocyte macrophage colony-stimulating factor (GM-CSF) secretion because this cytokine requires extracellular signalregulated kinase (ERK) signaling but is not highly calcium dependent, whereas interferon-␥ (IFN-␥), interleukin (IL)-4, and IL-2 production are minimal. Autoreactive activation was associated with reduced migration velocity but did not induce arrest; thus, NKT cells retained the ability to survey antigen presenting cells (APCs). IL-12 and IL-18 stimulated autoreactively activated NKT cells to secrete IFN-␥, and this was mediated by Janus kinase-signal transducers and activators of transcription (JAK-STAT)-dependent signaling without induction of calcium flux. This pathway did not require concurrent contact with CD1d ؉ APCs but was strictly dependent on preceding autoreactive stimulation that induced ERK activation. In contrast, NKT-cell responses to the glycolipid antigen ␣-galactosyl ceramide (␣-GalCer) were dampened by prior autoreactive activation. These results show that NKT-cell autoreactivity induces restricted cytokine secretion and leads to altered basal activation that potentiates innate responsiveness to costimulatory cytokines while modulating sensitivity to foreign antigens. (Blood. 2008;112: 4128-4138) IntroductionNatural killer T (NKT) cells are a subset of regulatory T cells that recognizes lipid antigens presented by CD1d molecules. 1,2 Like innate lymphocytes, NKT cells are among the first responders during microbial infections, and their responses are not necessarily dependent on recognition of foreign antigens. 3 NKT cells have attracted attention because they secrete large amounts of both Th1 and Th2 cytokines rapidly on stimulation and demonstrate a potent ability to modulate immune function. 1,2,4 Remarkably, in some disease models, NKT cells promote proinflammatory immune responses, whereas in others they have a tolerogenic effect. 5 It is not clear what confers the innate-like features of NKT cells or how they mediate contrasting immunologic outcomes in different contexts.Most NKT cells can be activated to secrete cytokines by exposure to CD1d ϩ antigen-presenting cells (APCs) in the absence of microbial antigens, and this appears to depend on presentation of cellular antigens by CD1d. 6-9 NKT cells from germ-free mice and from human cord blood display a phenotype indicating prior activation, [10][11][12] suggesting that NKT cells are autoreactive to self-antigens in vivo. NKT cells have been shown to recognize certain mammalian lipids as antigens presented by CD1d 9,13 ; however, the specific self-antigens responsible for NKT cell autorea...

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contrasting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Natural killer T-cell autoreactivity leads to a specialized activation state

Wang¹,

Chen²,

Rodenkirch

et al. 2008

Blood

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“…One study by Dr. M. L. Dustin's group has demonstrated that IL-12 might act on NKT cells directly; in this study the combination of IL-12 and IL-18 not only promoted NKT cells to produce IL-4 and IFN-␥ but also induced NKT cell arrest in liver sinusoids (32). Meanwhile, our study cannot exclude the possibility that IL-12 acts on other cell populations, such as sinusoidal endothelial cells, and then indirectly induces NKT cell recruitment by up-regulating chemokines or adherent molecules.…”

Section: Discussionmentioning

confidence: 61%

TLR-9 Activation Aggravates Concanavalin A-Induced Hepatitis via Promoting Accumulation and Activation of Liver CD4+ NKT Cells

Jiang

Sun

Zhou

et al. 2009

The Journal of Immunology

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Increasing evidence suggests that TLRs are involved in the pathogenesis of liver diseases; however, the underlying mechanisms remain obscure. In this study, we found that treatment with CpG-oligodeoxynucleotide (ODN) promoted the accumulation and activation of murine hepatic NKT cells. Additional experiments showed that CpG-ODN preferred to act on CD4+ NKT cells, while having less effect on CD4− NKT cells. The effect of CpG-ODN on liver NKT cells depended on the presence of Kupffer cells and IL-12. Meanwhile, CpG-ODN pretreatment aggravated liver injury and promoted the production of inflammatory cytokines in a Con A-induced fulminant hepatitis model via TLR9 activation. Collectively, our data demonstrate that TLR9 stimulation prefers to promote the accumulation and activation of hepatic CD4+ NKT cells and suggest that TLR9 signaling might be involved in the pathogenesis of human hepatitis.

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“…Intriguingly, the same investigators show that these iNKT cells stopped crawling when aGC was injected, suggesting that when activated, they engage with their Ag, presumably presented on CD1d. Other investigators have shown by intravital microscopy that activation of iNKT cells caused production of IL-12 and IL-18, which in turn induced cell arrest within liver sinusoids without a strict requirement for CD1d Ag presentation (46). This cell arrest behavior occurred within 1 h of cytokine exposure and precedes iNKT cell activation.…”

Section: Discussionmentioning

confidence: 87%

Involvement of the 4-1BB/4-1BBL Pathway in Control of Monocyte Numbers by Invariant NKT Cells

Cole

Benam

McMichael

et al. 2014

The Journal of Immunology

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4-1BB is expressed on invariant (i)NKT cells, but its role is unclear. We showed previously that iNKT cells are involved in control of monocyte numbers during influenza A virus (IAV) infection and now question the role of the 4-1BB costimulatory pathway in the cross-talk between these cells. We found that iNKT cells and monocytes interact to promote expression of 4-1BB and 4-1BBL, respectively. Blockade of 4-1BB/L pathway under resting coculture conditions increased apoptosis of iNKT cells and monocytes. However, activation of iNKT cells overrides this survival signal, causing marked apoptosis of monocytes independent of 4-1BB/L. Blocking 4-1BBL in alpha-galactosylceramide-activated iNKT–monocyte cocultures reduced iNKT proliferation and abrogated monocytic IL-12 production. In vivo, expression of 4-1BB and 4-1BBL is increased on iNKT cells and Ly6Chi monocytes, respectively, during IAV infection, and there were lower frequencies of apoptosing Ly6Chi monocytes in the blood of iNKT knockout mice and higher numbers of monocytes in lungs compared with infected wild-type mice. Adoptive transfer of iNKT cells into the lungs of these mice reduced lung Ly6Chi monocytes levels, even when iNKT cells were preincubated with 4-1BB blocking Abs. These findings suggest that under resting conditions, 4-1BB/L engagement during iNKT–monocyte interaction promotes survival of these cells. When iNKT cells are activated, whether by alpha-galactosylceramide or during IAV infection, iNKT cells induced apoptosis of monocytes via a 4-1BB/L–independent mechanism, reducing monocyte numbers. 4-1BB/L costimulation amplified monocyte-mediated proliferation of iNKT cells, indirectly providing a method for monocytes to control their own numbers during infection.

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Cutting Edge: Activation by Innate Cytokines or Microbial Antigens Can Cause Arrest of Natural Killer T Cell Patrolling of Liver Sinusoids

Cited by 77 publications

References 15 publications

Natural killer T-cell autoreactivity leads to a specialized activation state

Natural killer T-cell autoreactivity leads to a specialized activation state

TLR-9 Activation Aggravates Concanavalin A-Induced Hepatitis via Promoting Accumulation and Activation of Liver CD4+ NKT Cells

Involvement of the 4-1BB/4-1BBL Pathway in Control of Monocyte Numbers by Invariant NKT Cells

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