IL-15 and dendritic cells induce proliferation of CD4+CD25+ regulatory T cells from peripheral blood

Xu, Shuxiong; Sun, Zhaolin; Sun, Yan; Zhu, Jianguo; Li, Xiaowei; Zhang, Xinqi; Shan, Gang; Wang, Zhenxing; Liu, Hong; Wu, Xiongfei

doi:10.1016/j.imlet.2011.06.005

Cited by 9 publications

(9 citation statements)

References 35 publications

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“…These beneficial effects of IL-15 on T lymphocytes concur with the observation that human autoimmune disorders, including rheumatoid arthritis, psoriasis, and celiac diseases, are associated with the local overexpression of IL-15, which may favor a proinflammatory environment allowing autoreactive T cells to overcome the inhibition of functional Tregs (33–35). In contrast, other studies suggest that IL-15 can amplify both Treg number and suppressive function (37, 38), and contributes to their de novo generation (18, 32, 36–39, 51, 52). Finally, IL-2 −/− X IL-15 −/− mice show significantly decreased numbers of Tregs (31), and treatment with IL-15 promotes Treg activity sufficiently to protect natural killer–depleted non-obese diabetic mice against developing diabetes (38).…”

Section: Discussionmentioning

confidence: 86%

“…However, the proliferation and resistance to apoptosis mediated by IL-15 is greater in effector T cells than in Tregs, so that the net activity of effector T cells is increased, both in term of proliferative potential and cytotoxic activity. We and others (37) have shown that the IL-15Rα is expressed at low level both on Tregs and effector T cells, so that the differential effects of IL-15 on each subset likely lies in differences in downstream signaling and not on different expression levels of the receptor. IL-15 is also active when antigen-presenting cells trans-present the IL-15Rα, thus bypassing the need for IL-15Rα expression by target cells (53).…”

Section: Discussionmentioning

confidence: 89%

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Interleukin 15 Provides Relief to CTLs from Regulatory T Cell–Mediated Inhibition: Implications for Adoptive T Cell–Based Therapies for Lymphoma

Perna

Angelis

Pagliara

et al. 2013

Clinical Cancer Research

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Purpose Systemic administration of recombinant interleukin (IL)-2 is used to support the expansion and persistence of adoptively transferred antigen-specific CTLs in patients with cancer. However, IL-2 also expands regulatory T cells (Treg) that in turn impair the antitumor activity of CTLs. As recombinant IL-15 is approaching clinical applications, we assessed the effects of this cytokine on the proliferation and antitumor activity of CTLs in the presence of Tregs. We used the model of adoptive transfer of Epstein–Barr virus (EBV)-CTLs, as these cells induce responses in patients with EBV-associated Hodgkin lymphoma, and Tregs are frequently abundant in these patients. Experimental Design Tregs were isolated from the peripheral blood of healthy donors and patients with Hodgkin lymphoma or from Hodgkin lymphoma tumors and assessed for their ability to inhibit the proliferation and antitumor activity of EBV-CTLs in the presence of IL-15 or IL-2. Specific molecular pathways activated by IL-15 were also explored. Results We found that in the presence of Tregs, IL-15, but not IL-2, promoted the proliferation, effector function, and resistance to apoptosis of effectors T cells and EBV-CTLs. IL-15 did not reverse or block Tregs but instead preferentially supported the proliferation of CTLs and effector T cells as compared with Tregs. Conclusions IL-15 selectively favors the survival, proliferation, and effector function of antigen-specific CTLs in the presence of Tregs, and thus IL-15, unlike IL-2, would have a significant impact in sustaining expansion and persistence of adoptively transferred CTLs in patients with cancer, including those infused with EBV-CTLs for treatment of EBV-associated malignancies.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 89%

Interleukin 15 Provides Relief to CTLs from Regulatory T Cell–Mediated Inhibition: Implications for Adoptive T Cell–Based Therapies for Lymphoma

Perna

Angelis

Pagliara

et al. 2013

Clinical Cancer Research

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“…32 Conflicting reports exist on the role of IL-15 in the generation of T cells with regulatory functions. 17,18,33 Van Belle et al 15 has shown recently that in the presence of IL-15, the suppressive effects of Tregs was diminished in vitro. On the other hand, IL-15 has been shown to promote the development of CD4 1 CD25 1 FOXP3 1 Tregs in humans, 18 consistent with the fact that signaling via CD122 is required for the development of Tregs in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…14,15 Contrarily, other reports have shown that IL-15 supports the expansion of CD4 1 CD25 1 regulatory T cells. [16][17][18] While it is possible that IL-15 may influence both regulatory and target CD4 1 T-cell populations in vitro, the scenario may be different in vivo, where additional inflammatory mediators may modulate the effect of IL-15. For instance, even though the frequency of circulating regulatory T cells (Tregs) is increased in patients with rheumatoid arthritis, they are not capable of regulating the pathogenic process, in which IL-15 plays a key role.…”

Section: Introductionmentioning

confidence: 99%

IL-15 trans-presentation regulates homeostasis of CD4+ T lymphocytes

et al. 2014

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Interleukin-15 (IL-15) is essential for the survival of memory CD8(+) and CD4(+) T cell subsets, and natural killer and natural killer T cells. Here, we describe a hitherto unreported role of IL-15 in regulating homoeostasis of naive CD4(+) T cells. Adoptive transfer of splenocytes from non-obese diabetic (NOD) mice results in increased homeostatic expansion of T cells in lymphopenic NOD.scid.Il15(-/-) mice when compared to NOD.scid recipients. The increased accumulation of CD4(+) T cells is also observed in NOD.Il15(-/-) mice, indicating that IL-15-dependent regulation also occurs in the absence of lymphopenia. NOD.scid mice lacking the IL-15Rα chain, but not those lacking the common gamma chain, also show increased accumulation of CD4(+) T cells. These findings indicate that the IL-15-mediated regulation occurs directly on CD4(+) T cells and requires trans-presentation of IL-15. CD4(+) T cells expanding in the absence of IL-15 signaling do not acquire the characteristics of classical regulatory T cells. Rather, CD4(+) T cells expanding in the absence of IL-15 show impaired antigen-induced activation and IFN-γ production. Based on these findings, we propose that the IL-15-dependent regulation of the naive CD4(+) T-cell compartment may represent an additional layer of control to thwart potentially autoreactive cells that escape central tolerance, while permitting the expansion of memory T cells.

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“…Human immature DCs can stimulate the expansion of Tregs (19), but some degree of maturation leading to semimature DCs (30) yielded better results. In all protocols, there is a need for exogenous IL-2 to obtain optimal Treg expansion, but the requirements for exogenous cytokines may be different when mature monocyte-derived DCs (moDCs) are used as stimulator cells (31). In this study, we show that human allogeneic mature moDCs are superior stimulator cells to generate very potent alloantigenspecific nTregs in the presence of exogenous IL-15 only.…”

mentioning

confidence: 82%

Allogeneic Mature Human Dendritic Cells Generate Superior Alloreactive Regulatory T Cells in the Presence of IL-15

Litjens

Boer

Zuijderwijk

et al. 2015

The Journal of Immunology

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Expansion of Ag-specific naturally occurring regulatory T cells (nTregs) is required to obtain sufficient numbers of cells for cellular immunotherapy. In this study, different allogeneic stimuli were studied for their capacity to generate functional alloantigen-specific nTregs. A highly enriched nTreg fraction (CD4+CD25brightCD127− T cells) was alloantigen-specific expanded using HLA-mismatched immature, mature monocyte-derived dendritic cells (moDCs), or PBMCs. The allogeneic mature moDC-expanded nTregs were fully characterized by analysis of the demethylation status within the Treg-specific demethylation region of the FOXP3 gene and the expression of both protein and mRNA of FOXP3, HELIOS, CTLA4, and cytokines. In addition, the Ag-specific suppressive capacity of these expanded nTregs was tested. Allogeneic mature moDCs and skin-derived DCs were superior in inducing nTreg expansion compared with immature moDCs or PBMCs in an HLA-DR– and CD80/CD86-dependent way. Remarkably, the presence of exogenous IL-15 without IL-2 could facilitate optimal mature moDC-induced nTreg expansion. Allogeneic mature moDC-expanded nTregs were at low ratios (<1:320), potent suppressors of alloantigen-induced proliferation without significant suppression of completely HLA-mismatched, Ag-induced proliferation. Mature moDC-expanded nTregs were highly demethylated at the Treg-specific demethylation region within the FOXP3 gene and highly expressed of FOXP3, HELIOS, and CTLA4. A minority of the expanded nTregs produced IL-10, IL-2, IFN-γ, and TNF-α, but few IL-17–producing nTregs were found. Next-generation sequencing of mRNA of moDC-expanded nTregs revealed a strong induction of Treg-associated mRNAs. Human allogeneic mature moDCs are highly efficient stimulator cells, in the presence of exogenous IL-15, for expansion of stable alloantigen-specific nTregs with superior suppressive function.

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IL-15 and dendritic cells induce proliferation of CD4+CD25+ regulatory T cells from peripheral blood

Cited by 9 publications

References 35 publications

Interleukin 15 Provides Relief to CTLs from Regulatory T Cell–Mediated Inhibition: Implications for Adoptive T Cell–Based Therapies for Lymphoma

Interleukin 15 Provides Relief to CTLs from Regulatory T Cell–Mediated Inhibition: Implications for Adoptive T Cell–Based Therapies for Lymphoma

IL-15 trans-presentation regulates homeostasis of CD4+ T lymphocytes

Allogeneic Mature Human Dendritic Cells Generate Superior Alloreactive Regulatory T Cells in the Presence of IL-15

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