6.3.3 NK Cells in Health and Disease
As the largest lymphocyte population representing innate immunity, NK cells perform diverse functions.Through their ability to mediate killing and to produce soluble factors, NK cells perform multitudes of immunological functions.Counter-clockwise: bidirectional interactions between NK cell and dendritic cells (DCs)/macrophages result in priming.Activated DCs and macrophages generate interleukin (IL)-15, IL-12, IL-18, IL-35, IFN-α, IFN-β, IL-27, IL-1β, and IL-23.These, in turn, activate NK cells to be primed, proliferate, and to produce inflammatory factors and chemokines such as interferon-gamma (IFN-γ), granulocyte/monocyte colony-stimulating factor(GM-CSF), tumor necrosis factor (TNF)-α, CCL3, CCL4, and CCL5.In addition, IFN-γ from NK cells can increase the MHC class I expression and the transcription of genes encoding immuno-proteasomal subunits in these professional antigen-presenting cells and thereby augmenting T cell priming and activation.Similarly, virus-infected cells produce IFN-α, IFN-β, and IL-1β and present either “stress-induced” self-ligands or viral proteins on the cell surface that activate NK cells.A reduction in graft-versus-host disease (GvHD) is mediated through the production of IL-10 by the CD56brightCD16Neg NK cell subset and augmentation of GvT is potentiated via direct tumor killing by CD56dim CD16Pos NK cell subset.In addition, production of IL-22 by NK subsets may help the regeneration of epithelial cells in the mucosal tissues.Irrespective of these observations, the mechanisms by which NK cells are activated to respond during active GvHD/GvT is not fully understood.Genetic manipulation of NK cells has helped to improve the effector functionality and the longevity of human NK cells in vivo.Stable integration of gene encoding IL-15 into the genome of NK cells promotes sustained proliferation via an artificial autocrine loop.Similarly, integration of gene encoding IL-12 makes this cytokine abundantly available within the micro environmental milieu and thereby augment the effector functions of NK cells, specifically, the production of IFN-γ.
Augmented expression of NK cell activation receptors (NKRs) including NKG2D and NCR1 by genetic engineering increases the anti-tumor cytotoxicity of NK cells.Other studies have shown the expression of single chain variable fragment that forms the core ectodomain of chimeric antigen receptor (CAR) to augments the tumor-targeted killing of NK cells.These genetically modified NK cells provide exciting newer opportunities for cell-based therapies.The bidirectional interaction between NK and T cells results in the regulation of adaptive immunity.IL-2 produced by CD4+Th1 cells play a vital role in the proliferation and expansion of NK cells.Although in vitro experiments consistently have provided support toward this notion, the in vivo evidence is far from convincing.However, the inflammatory factors produced by NK cells have a significant impact on both CD8+ and CD4+ T cells.Expression of “self ” ligands for NKG2D by T cells results in the recognition and killing of T cells by NK cells during GvHD and anti-viral responses.In addition, a cleaved soluble form of these ligands (MIC-A/B) is present in the serum of cancer patients.This, in turn, plays an important role in containing the effector functions of T cells via direct binding to the NKG2D receptor expressed on T cells.NK cells recognize bacteria-infected cells (such as epithelial cells) either using toll-like receptors (TLR) or by activated through soluble factors including aryl hydrocarbon receptor (Ahr).This results in the production of IFN-γ and IL-22 that helps with the reduction in bacterial load and regeneration of epithelial cells, respectively.NK cells can also directly mediate the lysis of bacteria using granzymes and perforin (Figure 6.9) [77].(https://www.daowen.com)
Figure 6.9 N atural kil ler (NK) cel ls in health and disease.As the largest lymphocyte population representing innate immunity, NK cells perform diverse functions.Through their ability to mediate killing and to produce soluble factors, NK cells perform multitudes of immunological functions.Counter-clockwise: bidirectional interactions between NK cell and dendritic cells (DCs)/macrophages result in priming.Activated DCs and macrophages generate interleukin (IL)-15, IL-12, IL-18, IL-35,IFN-α, IFN-β, IL-27, IL-1β, and IL-23.These, in turn, activate NK cells to be primed, proliferate, and to produce inflammatory factors and chemokines such as interferon-gamma (IFN-γ), granulocyte/monocyte colony-stimulating factor (GM-CSF), tumor necrosis factor (TNF)-α, CCL3, CCL4, and CCL5.In addition, IFN-γ from NK cells can increase the MHC class I expression and the transcription of genes encoding immuno-proteasomal subunits in these professional antigen-presenting cells and thereby augmenting T cell priming and activation.Similarly, virus-infected cells produce IFN-α, IFN-β, and IL-1β and present either “stress-induced” self-ligands or viral proteins on the cell surface that activate NK cells.A reduction in graft-versus-host disease (GvHD) is mediated through the production of IL-10 by the CD56brightCD16Neg NK cell subset and augmentation of GvT is potentiated via direct tumor killing by CD56dimCD16Pos NK cell subset.In addition, production of IL-22 by NK subsets may help the regeneration of epithelial cells in the mucosal tissues.Irrespective of these observations, the mechanisms by which NK cells are activated to respond during active GvHD/GvT is not fully understood.Genetic manipulation of NK cells has helped to improve the effector functionality and the longevity of human NK cells in vivo.Stable integration of gene encoding IL-15 into the genome of NK cells promotes sustained proliferation via an artificial autocrine loop.Similarly, integration of gene encoding IL-12 makes this cytokine abundantly available within the microenvironmental milieu and thereby augment the effector functions of NK cells, specifically, the production of IFN-γ.Augmented expression of NK cell activation receptors (NKRs) including NKG2D and NCR1 by genetic engineering increases the anti-tumor cytotoxicity of NK cells.Other studies have shown the expression of single chain variable fragment that forms the core ectodomain of chimeric antigen receptor (CAR) to augments the tumor-targeted killing of NK cells.These genetically modified NK cells provide exciting newer opportunities for cell-based therapies.The bidirectional interaction between NK and T cells results in the regulation of adaptive immunity.IL-2 produced by CD4+ Th1 cells play a vital role in the proliferation and expansion of NK cells.Although in vitro experiments consistently have provided support toward this notion, the in vivo evidence is far from convincing.However, the inflammatory factors produced by NK cells have a significant impact on both CD8+ and CD4+ T cells.Expression of “self” ligands for NKG2D by T cells results in the recognition and killing of T cells by NK cells during GvHD and anti-viral responses.In addition, a cleaved soluble form of these ligands (MIC-A/B) is present in the serum of cancer patients.This, in turn, plays an important role in containing the effector functions of T cells via direct binding to the NKG2D receptor expressed on T cells.NK cells recognize bacteria-infected cells (such as epithelial cells) either using toll-like receptors (TLR) or by activated through soluble factors including aryl hydrocarbon receptor (Ahr).This results in the production of IFN-γ and IL-22 that helps with the reduction in bacterial load and regeneration of epithelial cells,respectively.NK cells can also directly mediate the lysis of bacteria using granzymes and perforin.(Please scan the QR code on the Preface to get original color figures.)
Source: Abel A M, Yang C, Thakar M S, Malarkannan S.“Natural Killer Cells: Development, Maturation,and Clinical Utilization”.FrontiersinImmunology, 2018, 9:1869.