Interleukin-21 administration leads to enhanced antigen-specific T cell responses and natural killer cells in HIV-1 vaccinated mice

Ju, Bin; Li, Dan; Ji, Xiaolin; Liu, Jiandong; Peng, Hong; Wang, Shuo; Liu, Ying; Hao, Yanling; Yee, Cassian; Liang, Hua; Shao, Yiming

doi:10.1016/j.cellimm.2016.03.006

Cited by 8 publications

(7 citation statements)

References 40 publications

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“…In stark contrast, none of the residues identified to be on the surface in the ordered regions show evidence for positive selection, suggesting that the disordered state, but not the ligand accessibility, lead to increased molecular rates. An exception suitable for a more detailed study of three-dimensional properties of positively selected sites in IDPs is one of our candidate genes under positive selection, interleukin 21, a protein that plays a fundamental role in the innate and adaptive immune responses (Yi et al 2010;Ju et al 2016). Based on a partly resolved NMR structure of the disordered region, we pinpointed three residues under positive selection (Fig.…”

Section: Molecular Dynamics Of Positively Selected Target Sites In Il21mentioning

confidence: 99%

Human long intrinsically disordered protein regions are frequent targets of positive selection

et al. 2018

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Intrinsically disordered regions occur frequently in proteins and are characterized by a lack of a well-defined three-dimensional structure. Although these regions do not show a higher order of structural organization, they are known to be functionally important. Disordered regions are rapidly evolving, largely attributed to relaxed purifying selection and an increased role of genetic drift. It has also been suggested that positive selection might contribute to their rapid diversification. However, for our own species, it is currently unknown whether positive selection has played a role during the evolution of these protein regions. Here, we address this question by investigating the evolutionary pattern of more than 6600 human proteins with intrinsically disordered regions and their ordered counterparts. Our comparative approach with data from more than 90 mammalian genomes uses a priori knowledge of disordered protein regions, and we show that this increases the power to detect positive selection by an order of magnitude. We can confirm that human intrinsically disordered regions evolve more rapidly, not only within humans but also across the entire mammalian phylogeny. They have, however, experienced substantial evolutionary constraint, hinting at their fundamental functional importance. We find compelling evidence that disordered protein regions are frequent targets of positive selection and estimate that the relative rate of adaptive substitutions differs fourfold between disordered and ordered protein regions in humans. Our results suggest that disordered protein regions are important targets of genetic innovation and that the contribution of positive selection in these regions is more pronounced than in other protein parts.

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Section: Molecular Dynamics Of Positively Selected Target Sites In Il21mentioning

confidence: 99%

Human long intrinsically disordered protein regions are frequent targets of positive selection

et al. 2018

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“…Ju et al. reported that administration of IL-21 increases the frequency of NK cells in HIV-vaccinated mice ( 128 ). Garrido et al.…”

Section: Nk Cell–based Immune Interventions Provide a Promising Strat...mentioning

confidence: 99%

Negative Regulation and Protective Function of Natural Killer Cells in HIV Infection: Two Sides of a Coin

2022

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Natural killer (NK) cells play an important immunologic role, targeting tumors and virus-infected cells; however, NK cells do not impede the progression of human immunodeficiency virus (HIV) infection. In HIV infection, NK cells exhibit impaired functions and negatively regulate other immune cell responses, although NK cells can kill HIV-infected cells and thereby suppress HIV replication. Considerable recent research has emerged regarding NK cells in the areas of immune checkpoints, negative regulation, antibody-dependent cell-mediated cytotoxicity and HIV reservoirs during HIV infection; however, no overall summary of these factors is available. This review focuses on several important aspects of NK cells in relation to HIV infection, including changes in NK cell count, subpopulations, and immune checkpoints, as well as abnormalities in NK cell functions and NK cell negative regulation. The protective function of NK cells in inhibiting HIV replication to reduce the viral reservoir and approaches for enhancing NK cell functions are also summarized.

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“…This has raised controversy regarding the anti‐tumor role of IL‐21, as STAT3 knock‐out mice exhibit improved rejection of tumors that are known to be controlled primarily by NK cells . In contrast, exogenous IL‐21 was shown to enhance NK cells in vaccinated mice . IL‐21 has a differential effect on malignant lymphoid cell lines of B cell and T cell origin—it induces growth stimulation in B cell lines, but in T cell lines it promotes apoptosis through increased Bax, caspase‐3, and caspase‐8, but decreased Bcl‐2 expression .…”

Section: Development Of Il‐21 Feeder Cellsmentioning

confidence: 99%

“…58,59 In contrast, exogenous IL-21 was shown to enhance NK cells in vaccinated mice. 60 IL-21 has a differential effect on malignant lymphoid cell lines of B cell and T cell origin-it induces growth stimulation in B cell lines, but in T cell lines it promotes apoptosis through increased Bax, caspase-3, and caspase-8, but decreased Bcl-2 expression. 61 In the setting of cell therapy, IL-21 may enhance the generation of T cells and clinical efficacy of anti-melanoma TIL.…”

Section: De Velopment Of Il-21 Feeder Cell Smentioning

confidence: 99%

Cellular therapy: Adoptive immunotherapy with expanded natural killer cells

Lee

2019

Immunological Reviews

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Adoptive immunotherapy with natural killer cells was pioneered 30 years ago in human clinical trials with the development of cytokine‐induced killer cells—unfractionated peripheral blood mononuclear cell (PBMC) populations activated overnight with IL‐2. Higher doses were subsequently made possible through the advent of steady‐state apheresis, allowing the collection of PBMC numbers equivalent to an entire adult blood volume, and increased purity made feasible through magnetic CD3‐depletion and/or CD56‐selection methods. Still, these approaches rarely achieved clinical dosing above a single infusion of 108 NK cells/kg, except with substantial donor‐recipient size mismatch (eg, parents donating cells to children). To address this shortcoming, leukemia cell lines with NK cell‐like function or ex vivo expansion approaches centered on the homeostatic cytokine IL‐15 were developed. Here, we describe the development of an ex vivo expansion system based on a feeder cell expressing membrane‐bound IL‐21 that enables log‐phase growth of primary NK cells for many weeks without inducing senescence, and describe the biology, correlative science, and translation to clinical trials for patients with leukemia, brain tumors, and solid tumors.

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Interleukin-21 administration leads to enhanced antigen-specific T cell responses and natural killer cells in HIV-1 vaccinated mice

Cited by 8 publications

References 40 publications

Human long intrinsically disordered protein regions are frequent targets of positive selection

Human long intrinsically disordered protein regions are frequent targets of positive selection

Negative Regulation and Protective Function of Natural Killer Cells in HIV Infection: Two Sides of a Coin

Cellular therapy: Adoptive immunotherapy with expanded natural killer cells

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