IL-15 Is Expressed by Dendritic Cells in Response to Type I IFN, Double-Stranded RNA, or Lipopolysaccharide and Promotes Dendritic Cell Activation

Mattei, Fabrizio; Schiavoni, Giovanna; Belardelli, Filippo; Tough, David F.

doi:10.4049/jimmunol.167.3.1179

Cited by 383 publications

(325 citation statements)

References 73 publications

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“…Taken together, these findings suggest that a bone marrowderived cell capable of expressing both IL-15R␣ and IL-15 could regulate memory CD8 ϩ T cell responses. Because dendritic cells (DC) can express both IL-15R␣ and IL-15 following activation, they are likely candidates involved in IL-15 transpresentation (29). In support of this concept, DC-derived IL-15 is essential for the induction of delayed-type hypersensitivity responses in mice (30).…”

mentioning

confidence: 70%

IL-15 Transpresentation Augments CD8+ T Cell Activation and Is Required for Optimal Recall Responses by Central Memory CD8+ T Cells

Kokaji

Hockley

Kane

2008

The Journal of Immunology

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Although the adaptive immune system has a remarkable ability to mount rapid recall responses to previously encountered pathogens, the cellular and molecular signals necessary for memory CD8+ T cell reactivation are poorly defined. IL-15 plays a critical role in memory CD8+ T cell survival; however, whether IL-15 is also involved in memory CD8+ T cell reactivation is presently unclear. Using artificial Ag-presenting surfaces prepared on cell-sized microspheres, we specifically addressed the role of IL-15 transpresentation on mouse CD8+ T cell activation in the complete absence of additional stimulatory signals. In this study we demonstrate that transpresented IL-15 is significantly more effective than soluble IL-15 in augmenting anti-CD3ε-induced proliferation and effector molecule expression by CD8+ T cells. Importantly, IL-15 transpresentation and TCR ligation by anti-CD3ε or peptide MHC complexes exhibited synergism in stimulating CD8+ T cell responses. In agreement with previous studies, we found that transpresented IL-15 preferentially stimulated memory phenotype CD8+ T cells; however, in pursuing this further, we found that central memory (TCM) and effector memory (TEM) CD8+ T cells responded differentially to transpresented IL-15. TCM CD8+ T cells undergo Ag-independent proliferation in response to transpresented IL-15 alone, whereas TEM CD8+ T cells are relatively unresponsive to transpresented IL-15. Furthermore, upon Ag-specific stimulation, TCM CD8+ T cell responses are enhanced by IL-15 transpresentation, whereas TEM CD8+ T cell responses are only slightly affected, both in vitro and in vivo. Thus, our findings distinguish the role of IL-15 transpresentation in the stimulation of distinct memory CD8+ T cell subsets, and they also have implications for ex vivo reactivation and expansion of Ag-experienced CD8+ T cells for immunotherapeutic approaches.

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mentioning

confidence: 70%

IL-15 Transpresentation Augments CD8+ T Cell Activation and Is Required for Optimal Recall Responses by Central Memory CD8+ T Cells

Kokaji

Hockley

Kane

2008

The Journal of Immunology

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“…Most interestingly, IL-15 is produced by dendritic cells upon stimulation with IFN type I. 41 This cytokine is not only frequently used in the treatment of metastatic melanoma but it has also been shown to provide adjuvancy in the induction of humoral and CTL responses [42][43][44] and to promote in experimental models of infection or cancer, the expansion of CD8þ T cells with a memory phenotype. 45 These immunoregulatory effects might be, at least in part, attributed the induction of paracrine IL-15 production.…”

Section: Discussionmentioning

confidence: 99%

Selective responsiveness to common gamma chain cytokines in peripheral blood‐derived cytotoxic T lymphocytes induced by Melan‐A/MART‐1_27–35targeted active specific immunotherapy

Holzen

Adamina

Bolli

et al. 2005

Intl Journal of Cancer

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We have comparatively evaluated the proliferative response of CTL induced in metastatic melanoma patients upon immunization against Melan‐A/MART‐127–35 tumor associated antigen (TAA) to IL‐2, IL‐7 or IL‐15 cytokines, sharing a receptor common γ‐chain (cγ‐c cytokines). Twenty‐eight CTL clones were generated from CD8+ T cells obtained from 3 patients during the contraction phase of immune response following a successful vaccine mediated expansion of specific effectors. All clones were able to kill tumor cell lines expressing HLA‐A0201 and Melan‐A/MART‐1, and displayed phenotypic characteristics of effector/memory (CD45RA−/CCR7−) or CD45RA+/CCR7− effector cells in intermediate to late developmental stage (CD28−/CD276±) CTL. Proliferative responses could be elicited or enhanced by IL‐2 and IL‐15, but not IL‐7, in the absence or in the presence of T‐cell receptor (TCR) triggering, respectively. Accordingly, only IL‐2 and IL‐15 were able to promote the survival of the CTL clones under investigation. While all clones expressed high amounts of receptor cγ‐c (CD132), lower, but detectable, expression of IL‐7 receptor alpha chain was also observed. CD8+ cells from one of the patients treated were obtained 6 months after the last vaccine boost and were cultured in the presence of Melan‐A/MART‐127–35 and each of the 3 cytokines under investigation. Consistent with data from CTL clones, expansion of Melan‐A/MART‐127–35 tetramer positive cells was only observed in the presence of IL‐2 or IL‐15 but not IL‐7. Instead, when CD8+ cells from the same patient were sampled shortly (14 days) after an additional vaccination only IL‐2 was able to promote the expansion of Melan‐A/MART‐127–35 tetramer positive cells. Taken together these data suggest a selective responsiveness of TAA‐specific CTL to different cγ‐c cytokines. © 2005 Wiley‐Liss, Inc.

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“…Type I IFNs stimulate murine DCs to produce cytokines such as IL-6 (17, 28) and IL-15 (32,33), although they do not induce classic proinflammatory cytokines like IL-12 (34). In Fig.…”

Section: Il-4 Suppresses the Expression Of Ifn-responsive Genes In Bmmentioning

confidence: 97%

IL-4 Suppresses Dendritic Cell Response to Type I Interferons

Sriram

Biswas

Behrens

et al. 2007

The Journal of Immunology

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Cytokines play an important role in modulating the development and function of dendritic cells (DCs). Type I IFNs activate DCs and drive anti-viral responses, whereas IL-4 is the prototype of a Th2 cytokine. Evidence suggests that type I IFNs and IL-4 influence each other to modulate DC functions. We found that two type I IFNs, IFN-α and IFN-β, stimulated a similar costimulatory profile in myeloid resting DCs. IL-4 suppressed the response of myeloid DCs to both type I IFNs in vitro and in vivo by impairing the up-regulation of MHC and costimulatory molecules and the production of cytokines, such as IL-6 and IL-15, and anti-viral genes, such as Mx-1, upon type I IFN stimulation. In dissecting the mechanism underlying this inhibition, we characterized the positive feedback loop that is triggered by IFN-α in primary DCs and found that IL-4 inhibited the initial phosphorylation of STAT1 and STAT2 (the transducers of signaling downstream of IFN-α and -β receptors (IFNARs)) and reduced the up-regulation of genes involved in the amplification of the IFN response such as IRF-7, STAT1, STAT2, IFN-β, and the IFNARs in vitro and in vivo. Therefore, IL-4 renders myeloid DCs less responsive to paracrine type I IFNs and less potent in sustaining the autocrine positive loop that normally amplifies the effects of type I IFNs. This inhibition could explain the increased susceptibility to viral infections observed during Th2-inducing parasitoses.

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IL-15 Is Expressed by Dendritic Cells in Response to Type I IFN, Double-Stranded RNA, or Lipopolysaccharide and Promotes Dendritic Cell Activation

Cited by 383 publications

References 73 publications

IL-15 Transpresentation Augments CD8+ T Cell Activation and Is Required for Optimal Recall Responses by Central Memory CD8+ T Cells

IL-15 Transpresentation Augments CD8+ T Cell Activation and Is Required for Optimal Recall Responses by Central Memory CD8+ T Cells

Selective responsiveness to common gamma chain cytokines in peripheral blood‐derived cytotoxic T lymphocytes induced by Melan‐A/MART‐1_27–35targeted active specific immunotherapy

IL-4 Suppresses Dendritic Cell Response to Type I Interferons

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IL-15 Is Expressed by Dendritic Cells in Response to Type I IFN, Double-Stranded RNA, or Lipopolysaccharide and Promotes Dendritic Cell Activation

Cited by 383 publications

References 73 publications

IL-15 Transpresentation Augments CD8+ T Cell Activation and Is Required for Optimal Recall Responses by Central Memory CD8+ T Cells

IL-15 Transpresentation Augments CD8+ T Cell Activation and Is Required for Optimal Recall Responses by Central Memory CD8+ T Cells

Selective responsiveness to common gamma chain cytokines in peripheral blood‐derived cytotoxic T lymphocytes induced by Melan‐A/MART‐127–35targeted active specific immunotherapy

IL-4 Suppresses Dendritic Cell Response to Type I Interferons

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Selective responsiveness to common gamma chain cytokines in peripheral blood‐derived cytotoxic T lymphocytes induced by Melan‐A/MART‐1_27–35targeted active specific immunotherapy