IL-15Rα chaperones IL-15 to stable dendritic cell membrane complexes that activate NK cells via trans presentation

Mortier, Erwan; Woo, Tammy T.; Advincula, Rommel; Gozalo, Sara; Ma, Averil

doi:10.1084/jem.20071913

Cited by 270 publications

(330 citation statements)

References 45 publications

Supporting

Mentioning

315

Contrasting

Unclassified

Order By: Relevance

“…However, IL-15 is known to be essentially trans-presented as a bioactive IL-15/IL15Ra complex by producing cells to neighboring cells bearing the IL-2/IL-15Rb and the g c chains. 22,23 In agreement, the protective effect of monocytes on B cells was significantly reinforced in the presence of exogeneous IL-15, suggesting that resting B cells could directly respond to IL-15-presenting cells.…”

Section: Monocytes/macrophages Efficiently Trans-present Il-15 To B Csupporting

confidence: 55%

Monocytes and T cells cooperate to favor normal and follicular lymphoma B-cell growth: role of IL-15 and CD40L signaling

et al. 2011

View full text Add to dashboard Cite

Interleukin-15 (IL-15) has been extensively studied for its role in the survival and proliferation of NK and T cells through a unique mechanism of trans-presentation by producer cells. Conversely, whereas activated B cells have been described as IL-15-responding cells, the cellular and molecular context sustaining this effect remains unexplored. In this study, we found that, whereas human B cells could not respond to soluble IL-15, monocytes and lymphoid tissue-derived macrophages but not stromal cells efficiently trans-present IL-15 to normal B cells and cooperate with T-cell-derived CD40L to promote IL-15-dependent B-cell proliferation. Furthermore, CD40L signaling triggers a Src-independent upregulation of STAT5 expression and favors a Src-dependent phosphorylation of STAT5 in response to IL-15. In follicular lymphoma (FL), immunohistochemical studies reported a strong relationship between malignant B cells, infiltrating macrophages and T cells. We show here an overexpression of IL-15 in purified tumor-associated macrophages, and STAT5A in purified tumor B cells. Moreover, FL B cells respond to IL-15 trans-presented by monocytes/macrophages, in particular, in the presence of CD40L-mediated signaling. This cooperation between IL-15 and CD40L reinforces the importance of tumor microenvironment and unravels a mechanism of FL growth that should be considered if using IL-15 as a drug in this disease.

show abstract

Section: Monocytes/macrophages Efficiently Trans-present Il-15 To B Csupporting

confidence: 55%

Monocytes and T cells cooperate to favor normal and follicular lymphoma B-cell growth: role of IL-15 and CD40L signaling

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Ligation of NK-cell receptors could be responsible for this contact dependency [15]; however, the formation of an immunological synapse could also be an important factor [39]. Next to IL-18, other possible candidates are MICA/B [15] and in trans presented IL-15 [15,28]. The functional consequence of NK-cell activation by IFN-g/FMKp-matured DC appeared to be dual.…”

Section: Discussionmentioning

confidence: 99%

“…This phenomenon was observed in both autologous as well as killer cell immunoglobulin-like receptor (KIR) mismatched NK-DC cocultures. A candidate cytokine responsible for this contact-dependent increase of IFN-g production is IL-15, which can be presented in trans by DC [15,28]. Therefore, expression of IL-15 by IFN-g/FMKp and TNF-a/PGE2-matured DC was evaluated by flow cytometry.…”

Section: Nk-cell Activation By Ifn-c/fmkp-stimulated DC Enhances Nk-cmentioning

confidence: 99%

See 1 more Smart Citation

Klebsiella pneumoniae‐triggered DC recruit human NK cells in a CCR5‐dependent manner leading to increased CCL19‐responsiveness and activation of NK cells

et al. 2010

View full text Add to dashboard Cite

Besides their role in destruction of altered self-cells, NK cells have been shown to potentiate T-cell responses by interacting with DC. To take advantage of NK-DC crosstalk in therapeutic DC-based vaccination for infectious diseases and cancer, it is essential to understand the biology of this crosstalk. We aimed to elucidate the in vitro mechanisms responsible for NK-cell recruitment and activation by DC during infection. To mimic bacterial infection, DC were exposed to a membrane fraction of Klebsiella pneumoniae, which triggers TLR2/4. DC matured with these bacterial fragments can actively recruit NK cells in a CCR5-dependent manner. An additional mechanism of DC-induced NK-cell recruitment is characterized by the induction of CCR7 expression on CD56 dim CD16 1 NK cells after physical contact with membrane fraction of K. pneumoniae-matured DC, resulting in an enhanced migratory responsiveness to the lymph node-associated chemokine CCL19. Bacterial fragment-matured DC do not only mediate NK-cell migration but also meet the prerequisites needed for augmentation of NK-cell cytotoxicity and IFN-c production, the latter of which contributes to Th1 polarization.Key words: CCR5 . CCR7 . NK-DC interaction . Th1 polarization Supporting Information available online Introduction NK cells are important effector cells in the innate immune response against virally infected or malignantly transformed cells and their cytotoxicity is regulated by a delicate balance of inhibitory and activating signals [1]. Recent studies suggest that the interplay between NK cells and DC, the specialized antigenpresenting cell of the innate immune system [2], is critical in shaping the adaptive immune response [3]. This concept originates from several lines of evidence including: the discovery of NK cells colocalizing with DC in the T-cell areas of lymph nodes [4,5], the coupling of NK-cell recruitment to lymph nodes Ã These authors contributed equally to this work. 3138with the induction of more potent Th1 skewing [3], and the identification of NK-cell subpopulations with helper properties [6]. Although the exact mechanisms of NK-DC interaction remain to be elucidated, increasing evidence supports the importance of bidirectional NK-DC crosstalk [7,8].On the one hand, NK-DC crosstalk is characterized by the capacity of activated NK cells to induce DC maturation with elevated IL-12p70 production and subsequently an increased capacity to induce Th1 and CTL responses [9]. This NK-induced DC maturation depends at least in part on soluble factors such as and as well as on engagement of the natural cytotoxicity triggering receptor 30 [12]. Moreover, NK cells control the quality of the adaptive immune response by natural cytotoxicity triggering receptor 30-mediated lysis of immature or inadequately matured DC [13], enabling only fully mature DC to migrate into lymph nodes and subsequently prime T cells. On the other hand, DC are able to induce NK-cell proliferation, augmentation of cytotoxicity and cytokine secretion [8]. The DC-induced modulati...

show abstract

“…3A), we examined the NK cell response in total splenocyte culture. As LPS-or CpG-activated murine DCs trans-present IL-15 to prime NK cells (26,27,31,32), we first determined whether IL15Ra on splenocytes affects the NK cell response in the absence of microbial stimulation. WT and KO NK cells expressed a similar level of surface NK1.1 before stimulation (Supplemental Table I).…”

Section: The Level Of Il-15 Trans-presentation By Accessory Cells Posmentioning

confidence: 99%

Different NK Cell Developmental Events Require Different Levels of IL-15 Trans-Presentation

Lee

Liou

Wang

et al. 2011

The Journal of Immunology

View full text Add to dashboard Cite

NK cell development requires IL-15, which is “trans-presented” to IL-15Rβγ on NK cells by IL-15Rα on other cells. In this study, we report that different levels of IL-15 trans-presentation are required for different NK cell developmental events to reach full maturation status. Because the IL-15Rα intracellular domain has the capacity to recruit signaling molecules, we generated knockin and transgenic (Tg) mice that lack the intracellular domain to assess the role of the IL-15 trans-presentation level independent of the function of this domain. The level of IL-15Rα on various cells of these mice follows the order WT > Tg6 > knockin > Tg1 ≥ knockout. Bone marrow (BM)–derived dendritic cells prepared from these mice induced Stat5 phosphorylation in NK cells. The level of phospho-Stat5 correlated with the level of IL-15Rα on BMDCs, thus offering the opportunity to study quantitative effects of IL-15 trans-presentation on NK cell development in vivo. We found that NK cell homeostasis, mature NK cell differentiation, and acquisition of Ly49 receptor and effector functions require different levels of IL-15 trans-presentation input to achieve full status. All NK cell developmental events examined were quantitatively regulated by the IL-15Rα level of BM-derived and radiation-resistant accessory cells, but not by IL-15Rα of NK cells. We also found that IL-15Rα of radiation-resistant cells was more potent than IL-15Rα of BM-derived accessory cells in support of stage 2 to stage 3 splenic mNK differentiation. In summary, each examined developmental event required a particular level of IL-15 trans-presentation by accessory cells.

show abstract

IL-15Rα chaperones IL-15 to stable dendritic cell membrane complexes that activate NK cells via trans presentation

Cited by 270 publications

References 45 publications

Monocytes and T cells cooperate to favor normal and follicular lymphoma B-cell growth: role of IL-15 and CD40L signaling

Monocytes and T cells cooperate to favor normal and follicular lymphoma B-cell growth: role of IL-15 and CD40L signaling

Klebsiella pneumoniae‐triggered DC recruit human NK cells in a CCR5‐dependent manner leading to increased CCL19‐responsiveness and activation of NK cells

Different NK Cell Developmental Events Require Different Levels of IL-15 Trans-Presentation

Contact Info

Product

Resources

About