Effect of IL-21 on NK cells derived from different umbilical cord blood populations

Perez, Sonia A.; Mahaira, Louisa G.; Sotiropoulou, Panagiota A.; Gritzapis, Angelos D.; Iliopoulou, Eleni G.; Niarchos, Dimitrios K.; Cacoullos, Nike T.; Kavalakis, Yannis G.; Antsaklis, Aris; Sotiriadou, Nectaria N.; Baxevanis, Constantin N.; Papamichail, Michael

doi:10.1093/intimm/dxh348

Cited by 39 publications

(27 citation statements)

References 35 publications

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“…6). This is consistent with the recently reported ability of IL-21 to increase secretion of IL-10 by human PBMC stimulated with anti-CD40 mAb (58) and cytokinestimulated human and mouse NK cells (60,61), respectively. However, the same caveats apply to the effects of IL-21 on cytokine secretion by CD40-stimulated human PBMC as those detailed above for proliferation, because it is possible that monocytes, which constitutively express CD40 and respond to activation with CD40L by secreting cytokines (64), were responsible for the IL-10 secretion noted in these cultures (58).…”

Section: Discussionsupporting

confidence: 92%

“…In contrast, we isolated B cell subsets by sorting such that the purity was usually Ͼ97%. Thus, because IL-21 has pleiotropic effects on other cell types, such as T cells and NK cells (23,25,60,61) that would still be present in these cultures, the apparent increase in anti-CD40 mAb-induced B cell proliferation observed in the presence IL-4, IL-10, or IL-13 may result from an indirect effect of IL-21 on T cells and NK cells. Similarly, IL-4, IL-10, and IL-13 can all influence the behavior of monocytes, with respect to phenotype and cytokine secretion (62).…”

Section: Discussionmentioning

confidence: 99%

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Kinetics of Human B Cell Behavior and Amplification of Proliferative Responses following Stimulation with IL-21

Good

Bryant

Tangye

2006

The Journal of Immunology

250

237

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Although recent studies indicated that IL-21 is an important regulator of human B cell activation, detailed comparison of the effects of IL-21 on distinct B cell subsets have not been performed. Our studies revealed that IL-21R is expressed by naive and germinal center B cells, but not memory or plasma cells. IL-21R was increased on naive and memory B cells following in vitro activation. Investigation into the kinetics and magnitude of responses of human B cells to IL-21 revealed that IL-21 potently augmented proliferation of CD40L-stimulated neonatal, splenic naive, and memory and tonsil germinal center B cells. This response exceeded that induced by IL-4, IL-10, and IL-13, cytokines that also induce B cell proliferation. Remarkably, CD40L/IL-21-stimulated naive B cells underwent the same number of divisions as memory cells and exhibited a greater enhancement in their response compared with CD40L alone than memory B cells. Therefore, IL-21 is a powerful growth factor for naive B cells. This may result from the higher expression of IL-21R on naive, compared with memory, B cells. Stimulation of human B cells with CD40L/IL-21 also induced IL-10 production and activation of STAT3. We propose that IL-21 may have therapeutic application in conditions of immunodeficiency where it could expand naive B cells, the predominant B cell subset in such patients. Conversely, because IL-21 is increased in murine models of lupus, dysregulated IL-21 production may contribute to perturbed B cell homeostasis observed in systemic lupus erythematosus. Thus, antagonizing IL-21 may be a novel strategy for treating Ab-mediated autoimmune diseases.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Kinetics of Human B Cell Behavior and Amplification of Proliferative Responses following Stimulation with IL-21

Good

Bryant

Tangye

2006

The Journal of Immunology

250

237

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“…These include cytokines such as IFN-c, IL-10, T-bet, and granulocyte macrophage colony-stimulating factor (GM-CSF; refs. 35,43,44) and gene products involved in interactions with cells of the adaptive immune system, including MyD88, IL-2Ra/CD25, IL-12Rh2, and IL-18R (10,35). IL-21 also enhances antibody-dependent cellular cytotoxicity by NK cells, leading to secretion of IFN-g, tumor necrosis factor-a, IL-8, macrophage inflammatory protein-1a, and regulated on activation, normal T-cell expressed and secreted (RANTES), and to an enhanced antitumor effect (45).…”

Section: Interactions Of Il-21 On Various Cell Typesmentioning

confidence: 99%

Interleukin-21 Signaling: Functions in Cancer and Autoimmunity

Davis

Skak

Smyth

et al. 2007

Clinical Cancer Research

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) is a cytokine with structural and sequence homology to IL-2 and IL-15, yet possesses several biological properties distinct from these cytokines. IL-21is produced mainly by activated CD4 + T cells and natural killer T cells and mediates its activity by binding to the IL-21 receptor (IL-21R), consisting of an IL-21^specific a chain (IL-21Ra; JAK/STAT) that heterodimerizes with the common g chain (CD132). Intracellular signaling occurs through the Janus-activated kinase/signal transducer and activator of transcription pathways. Physiologic expression of IL-21R is restricted to lymphoid tissues and peripheral blood mononuclear cells; however, other tissues such as epithelium, synovium, or transformed cells can acquire expression of both components of IL-21R heterodimer. IL-21has complex activities on a wide variety of cell types, leading to enhancement of adaptive T-cell immunity, antibody production, activation of natural killer cell subtypes, and opposition to suppressive effects mediated by regulatory T cells. Functionally, these activities promote immune responses and point to a physiologic role of IL-21in autoimmunity and immune enhancement. Therapeutic manipulation of IL-21 activity may allow improved immunotherapy for cancer as well as insights into autoimmune disease. Recently conducted phase1trials in metastatic melanoma and renal cell carcinoma have shown that recombinant IL-21 has a favorable safety profile and support its continued investigation as a potential anticancer drug.

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“…The discovery of IL-21 was linked to its role in proliferation and maturation of NK cells [49], but subsequent studies have been widely disparate, identifying it as both activating and suppressive [50], [51], [52]. Although soluble IL-21 alone does not induce significant proliferation of mature murine NK cells and IL-21R knockout mice have normal NK cell numbers [50], IL-21 synergizes with IL-2, IL-15, and Flt-3L in the generation of NK cells from bone marrow [49] and cord blood [49], [53], [54], [55], [56]. IL-21 may activate NK cell lytic activity through upregulation of costimulatory receptors, perforin, and granzyme [57].…”

Section: Introductionmentioning

confidence: 99%

Membrane-Bound IL-21 Promotes Sustained Ex Vivo Proliferation of Human Natural Killer Cells

et al. 2012

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NK cells have therapeutic potential for a wide variety of human malignancies. However, because NK cells expand poorly in vitro, have limited life spans in vivo, and represent a small fraction of peripheral white blood cells, obtaining sufficient cell numbers is the major obstacle for NK-cell immunotherapy. Genetically-engineered artificial antigen-presenting cells (aAPCs) expressing membrane-bound IL-15 (mbIL15) have been used to propagate clinical-grade NK cells for human trials of adoptive immunotherapy, but ex vivo proliferation has been limited by telomere shortening. We developed K562-based aAPCs with membrane-bound IL-21 (mbIL21) and assessed their ability to support human NK-cell proliferation. In contrast to mbIL15, mbIL21-expressing aAPCs promoted log-phase NK cell expansion without evidence of senescence for up to 6 weeks of culture. By day 21, parallel expansion of NK cells from 22 donors demonstrated a mean 47,967-fold expansion (median 31,747) when co-cultured with aAPCs expressing mbIL21 compared to 825-fold expansion (median 325) with mbIL15. Despite the significant increase in proliferation, mbIL21-expanded NK cells also showed a significant increase in telomere length compared to freshly obtained NK cells, suggesting a possible mechanism for their sustained proliferation. NK cells expanded with mbIL21 were similar in phenotype and cytotoxicity to those expanded with mbIL15, with retained donor KIR repertoires and high expression of NCRs, CD16, and NKG2D, but had superior cytokine secretion. The mbIL21-expanded NK cells showed increased transcription of the activating receptor CD160, but otherwise had remarkably similar mRNA expression profiles of the 96 genes assessed. mbIL21-expanded NK cells had significant cytotoxicity against all tumor cell lines tested, retained responsiveness to inhibitory KIR ligands, and demonstrated enhanced killing via antibody-dependent cell cytotoxicity. Thus, aAPCs expressing mbIL21 promote improved proliferation of human NK cells with longer telomeres and less senescence, supporting their clinical use in propagating NK cells for adoptive immunotherapy.

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Effect of IL-21 on NK cells derived from different umbilical cord blood populations

Cited by 39 publications

References 35 publications

Kinetics of Human B Cell Behavior and Amplification of Proliferative Responses following Stimulation with IL-21

Kinetics of Human B Cell Behavior and Amplification of Proliferative Responses following Stimulation with IL-21

Interleukin-21 Signaling: Functions in Cancer and Autoimmunity

Membrane-Bound IL-21 Promotes Sustained Ex Vivo Proliferation of Human Natural Killer Cells

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