Distinct roles of IL-12 and IL-15 in human natural killer cell activation by dendritic cells from secondary lymphoid organs

Ferlazzo, Guido; Pack, Maggi; Thomas, Dolca; Paludan, Casper; Schmid, Dorothee; Strowig, Till; Bougras, Gwenola; Müller, William A.; Moretta, Lorenzo; Münz, Christian

doi:10.1073/pnas.0407522101

Cited by 505 publications

(555 citation statements)

References 38 publications

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“…However, IL-15 induces only CD56 dim -like levels of CD56, CD16 and KIR in CD56 bright in contact with fibroblasts [20] or after infusion of CD56 bright into immune-deficient mice [20,21]. Furthermore, skewing NK-cell differentiation toward CD56 dim is far superior when IL-15 is trans-presented by IL-15Ra-Fc [21], which mimics the way IL-15 is presented by dendritic cells to NK cells in lymph nodes [22]. Although these results provide direct evidence that a transition of CD56 bright to CD56 dim may occur, it remains unclear to what extent this transition represents the typical differentiation pathway in vivo.…”

Section: Introductionmentioning

confidence: 99%

CD56^bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells

et al. 2010

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We studied early NK-cell recovery in 29 allografted patients undergoing different lymphoreductive regimens. Already at 2 wk after graft take, the number of NK cells had reached (supra)normal levels but NK-cell subsets were skewed. The number of CD56 dim CD16 bright NK cells was low and correlated strongly with the level of hematopoiesis, whereas the number of the more abundant NK cells expressing high levels of CD56 did not. Post-transplant CD56 bright NK cells (ptCD56 bright ) differed from CD56 bright NK cells in normal controls (CD56 bright ) in being HLA-DR-and perforin-positive, CCR7 À , CD27 À , CD127 À and mostly c-kit À . CD56 bright from normal controls stimulated by IL-15 in vitro (NK ) acquired all the characteristics distinguishing CD56 bright from ptCD56 bright . IL-2 exerted similar effects. Moreover, when cultured without cytokines, ptCD56 bright , CD56 bright and NK responded similarly by upregulating CD127 and c-kit but not CCR7. IL-12 stimulated IFN-c production in ptCD56 bright , whereas CD56 bright responded only to IL-12 plus IL-15. Hence, ptCD56 bright have all the features of cytokine-stimulated CD56 bright . Because only patients with low numbers of T cells had high numbers of ptCD56 bright , we conclude that ptCD56 bright are activated CD56 bright that expand while competing with T cells for the elevated post-transplant level of IL-15.Key words: HSC transplantation . Human . Natural killer cells IntroductionIn humans, most lymphocytes without rearranged antigenreceptors express CD56 and are referred to as NK cells. Accordingly, they can be identified on the basis of a CD3 À CD56 1 phenotype [1][2][3], which excludes the subpopulation of T cells that coexpress CD56. However, this long-established definition of NK cells may be inadequate because CD3 À CD56 1 lymphocytes are heterogeneous and capable of exerting various effector functions other than killing cells with altered expression of self-MHC. Furthermore, many CD3 À CD56 1 lymphocytes do not lyse NK-cell targets when tested ex vivo and only acquire lytic activity after in vitro stimulation with cytokines. In fact, the large granular CD3 À CD56 1 lymphocytes with ''natural'' cytotoxicity that express low levels of CD56 (CD56 dim ) and high levels of the Fcg-receptor type III (CD16) [1][2][3][4] represent only a minority of all of the CD3 À CD56 1 lymphocytes in the body [5,6]. CD56 dim that provide first-line defense against viruses [7,8] 3246less abundant population of NK cells in peripheral blood expresses much higher levels of CD56 (CD56 bright ), the receptor for IL-7 (CD127), the receptor for SCF c-kit, the lymph nodehoming receptor CCR7, and displays only little cytolytic activity [3][4][5][9][10][11][12]. Approximately, half of the CD56 bright in peripheral blood express CD27, a marker virtually absent from CD56 dim [13][14][15]. Hence, CD56 bright in peripheral blood are identical or closely related to the NK cells residing in secondary lymphoid organs (SLO) that produce cytokines to guide the adaptive immune response [4-6,...

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Section: Introductionmentioning

confidence: 99%

CD56^bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells

et al. 2010

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“…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 with 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].…”

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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

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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...

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“…DCs and NK cells often colocalize and are able to interact both at sites of inflammation and in lymph nodes (25,26). In DC-NK cell interactions, cytokines, such as IL-12, IFN-a, and IL-15, are important, but direct cell-to-cell contacts also seem to be essential in promoting full NK activation by DCs (27). The CD56 bright CD16 2 subset can also act as accessory APCs via upregulated HLA-DR and secretion of IFN-g, thus enhancing CD4 T lymphocyte responses (28,29).…”

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Herpes Simplex Virus Antigens Directly Activate NK Cells via TLR2, Thus Facilitating Their Presentation to CD4 T Lymphocytes

Kim

Osborne

Zeng

et al. 2012

The Journal of Immunology

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NK cells infiltrate human herpetic lesions, but their role has been underexplored. HSV can stimulate innate immune responses via surface TLR2, which is expressed on monocyte-derived dendritic cells (DCs) and NK cells. In this study, UV-inactivated HSV1/2 and immunodominant HSV2 glycoprotein D peptides conjugated to the TLR2 agonist dipalmitoyl-S-glyceryl cysteine stimulated CD4 T lymphocyte IFN-γ responses within PBMCs or in coculture with monocyte-derived DCs. NK cells contributed markedly to the PBMC responses. Furthermore, NK cells alone were activated directly by both Ags, also upregulating HLA-DR and HLA-DQ and then they activated autologous CD4 T lymphocytes. Using Transwells, Ag-stimulated NK cells and CD4 T lymphocytes were shown to interact through both cell-to-cell contact and cytokines, differing in relative importance in different donors. A distinct immunological synapse between Ag-stimulated NK cells and CD4 T lymphocytes was observed, indicating the significance of their cell-to-cell contact. A large proportion (57%) of NK cells was also in contact with CD4 T lymphocytes in the dermal infiltrate of human recurrent herpetic lesions. Thus, NK cells stimulated by TLR2-activating HSV Ags can present Ag alone or augment the role of DCs in vitro and perhaps in herpetic lesions or draining lymph nodes. In addition to DCs, NK cells should be considered as targets for adjuvants during HSV vaccine development.

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Distinct roles of IL-12 and IL-15 in human natural killer cell activation by dendritic cells from secondary lymphoid organs

Cited by 505 publications

References 38 publications

CD56^bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells

CD56^bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells

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

Herpes Simplex Virus Antigens Directly Activate NK Cells via TLR2, Thus Facilitating Their Presentation to CD4 T Lymphocytes

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Distinct roles of IL-12 and IL-15 in human natural killer cell activation by dendritic cells from secondary lymphoid organs

Cited by 505 publications

References 38 publications

CD56bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells

CD56bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells

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

Herpes Simplex Virus Antigens Directly Activate NK Cells via TLR2, Thus Facilitating Their Presentation to CD4 T Lymphocytes

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CD56^bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells

CD56^bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells