iNKT Cells Require CCR4 to Localize to the Airways and to Induce Airway Hyperreactivity

Meyer, Everett; Wurbel, Marc‐André; Staton, Tracy; Pichavant, Muriel; Kan, Matthew J.; Savage, Paul B.; DeKruyff, Rosemarie H.; Butcher, Eugene C.; Campbell, James J.; Umetsu, Dale T.

doi:10.4049/jimmunol.179.7.4661

Cited by 48 publications

(40 citation statements)

References 48 publications

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“…The BALF of treated mice contained higher levels of thymus-and activation-regulated chemokine (TARC) (Supporting Information Fig. 2), also called CCL17, whose receptor CCR4 is known for its role in the recruitment of iNKT cells to the lung [22], which is consistent with their local effect in counteracting IL-33-promoted lung inflammation. By contrast, lung inflammation decreased when iNKT cell counts increased in Va14-Ja18 (Va14) Tg mice, which hampered disease syndromes (Supporting Information Fig.…”

Section: Results and Discussion Inkt-cell Deficiency Aggravates Il-33supporting

confidence: 52%

A natural protective function of invariant NKT cells in a mouse model of innate‐cell‐driven lung inflammation

et al. 2011

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Activation of invariant natural killer T (iNKT) cells by treatment with their a-galactosylceramide ligand provides therapeutic benefits in several immune inflammatory settings. Given the artificial nature of this stimulation, the natural regulatory functions of iNKT remain uncertain. Addressing this issue in a mouse model of innate-cell-driven lung inflammation induced by the cytokine/alarmin IL-33 that targets iNKT cells, we found that eosinophil and neutrophil recruitment was markedly increased in treated iNKT cell-deficient (Ja18 KO) mice, as was the local production of eotaxin and keratinocyte chemoattractant chemokines. By contrast, lung inflammation decreased after adoptive transfer of iNKT cells, which restored the WT inflammatory response in Ja18 KO mice. Finally, we established that this natural anti-inflammatory function of iNKT cells depends on their IFN-c production and on endogenous IL-12. Our study provides the first evidence of a protective role of iNKT cells during lung inflammation that does not require pharmacological TCR engagement.Keywords: IL-33 . Inflammation . iNKT cells . Innate cells Supporting Information available online IntroductionInvariant natural killer T (iNKT) cells constitute a population of T cells, which share some characteristics with NK cells. In this regard, they occupy a strategic position between adaptive and innate immunity. iNKT cells are characterized by the expression of an invariant Va14Ja18 antigen receptor, chiefly paired with Vb8.2 in mice and of the invariant Va24Ja18/Vb11 pair in humans (for reviews see [1,2] Frontline key regulatory functions, based on the therapeutic benefits provided by their specific exogenous ligand a-galactosyl ceramide (a-GC) in several models of autoimmunity and allergic asthma (for reviews see [5][6]) [7][8][9][10][11]. However, whether these cells actually play a regulatory role in these pathologies in the absence of pharmacological TCR engagement is still doubtful (for reviews see [6]). The answer to this fundamental question in iNKT cell biology has remained elusive since almost all pathological experimental models of autoimmunity and asthma require an immunization phase that presumably recruits and activates iNKT cells in a non-physiological rather than a disease-specific manner. Hence, there is still no definite evidence that iNKT cells specifically exert natural regulatory functions in the experimental allergic OVA-or ragweed-induced asthma model, in which iNKT cells can promote disease protection [10,11] or induction and/or exacerbation [12][13][14], depending on their mode of activation.Here, we used a novel approach to address this issue in a model of innate-cell-driven lung inflammation induced by , a cytokine that has recently been described as a member of the IL-1 family [16] and credited with alarmin functions [17][18][19]. This strategy is of pathophysiological relevance, considering the well-established role played by iNKT cells during allergic asthma together with the fact that they are effectively targeted and functiona...

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Section: Results and Discussion Inkt-cell Deficiency Aggravates Il-33supporting

confidence: 52%

A natural protective function of invariant NKT cells in a mouse model of innate‐cell‐driven lung inflammation

et al. 2011

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“…The mechanism by which this occurs makes use of CCL17, a molecule previously reported to be important to induce iNKT cell chemotaxis. In a previous study of airway hyper-responsiveness (AHR), mice deficient for CCR4 (CCL17 receptor) did not develop AHR (Meyer et al, 2007). The group concluded that the CCR4 receptor on iNKT cells was important for their localization in the lung (Meyer et al, 2007).…”

Section: Resultsmentioning

confidence: 98%

iNKT Cell Emigration out of the Lung Vasculature Requires Neutrophils and Monocyte-Derived Dendritic Cells in Inflammation

et al. 2016

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iNKT cells are a subset of innate T cells that recognize glycolipids presented on CD1d molecules and protect against a variety of bacterial infections including S. pneumoniae. Using lung intravital imaging, we examined the behavior and mechanism of pulmonary iNKT cell activation in response to the potent iNKT cell ligand α-galactosylceramide or during S. pneumoniae infection. In untreated mice the major fraction of iNKT cells resided in the vasculature, but a small critical population resided in the extravascular space in proximity to monocyte-derived DCs. Administration of either α-GalCer or S. pneumoniae, induced CD1d dependent rapid recruitment of neutrophils out of the vasculature. This neutrophil exodus paved the way for extravasation of iNKT cells from the lung vasculature via CCL17. Depletion of monocyte-derived DCs abrogated both the neutrophil and subsequent iNKT cell extravasation. Moreover, impairing iNKT cell migration out of the lung vasculature by blocking CCL17 greatly increased susceptibility to S. pneumoniae infection, suggesting a critical role for the secondary wave of iNKT cells in host defense.

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“…This includes the ability of CCL17 to antagonize Th1 responses [89] and activate Th17 cells, a lineage distinct from Th1 and Th2 cells that produces IL-17 and IL-22 [90,91] and express CCR4 [92]. Invariant CD1d-restricted natural killer T (iNKT) cells also express CCR4 on their surface, and CCR4 was found to be critical for the localization of these cells to the airways and the induction of airway hyperreactivity [93 ].…”

Section: Chemokine (C-c Motif) Ligand 17mentioning

confidence: 98%

Novel biomarkers in asthma: chemokines and chitinase-like proteins

Hartl

Lee

Silva

et al. 2009

Current Opinion in Allergy &Amp; Clinical Immunology

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iNKT Cells Require CCR4 to Localize to the Airways and to Induce Airway Hyperreactivity

Cited by 48 publications

References 48 publications

A natural protective function of invariant NKT cells in a mouse model of innate‐cell‐driven lung inflammation

A natural protective function of invariant NKT cells in a mouse model of innate‐cell‐driven lung inflammation

iNKT Cell Emigration out of the Lung Vasculature Requires Neutrophils and Monocyte-Derived Dendritic Cells in Inflammation

Novel biomarkers in asthma: chemokines and chitinase-like proteins

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