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Recognition and killing of aberrant, infected or tumor targets by Natural Killer (NK) cells is mediated by positive signals transduced by activating receptors upon engagement of ligands on target surface. These stimulatory pathways are counterbalanced by inhibitory receptors that raise NK cell activation threshold through negative antagonist signals. While regulatory effects are necessary for physiologic control of autoimmune aggression, they may restrain the ability of NK cells to activate against disease. Overcoming this barrier to immune surveillance, multiple approaches to enhance NK-mediated responses are being investigated since two decades. Propelled by considerable advances in the understanding of NK cell biology, these studies are critical for effective translation of NK-based immunotherapy principles into the clinic. In humans, dominant inhibitory signals are transduced by Killer Immunoglobulin Like Receptors (KIR) recognizing cognate HLA class I on target cells. Conversely, KIR recognition of “missing self-HLA” - due to HLA loss or HLA/ KIR mismatch - triggers NK-mediated tumor rejection. Initially observed in murine transplant models, these antitumor effects were later found to have important implications for the clinical outcome of haplotype-mismatched stemcell transplantation. Here, donor NK subsets protect against acute myeloid leukemia (AML) relapse through missing self recognition of donor HLA-C allele groups (C1 or C2) and/or Bw4 epitope. These studies were subsequently extended by trials investigating the antileukemia effects of adoptively transferred haplotype-mismatched NK cells in non-transplant settings. Other mechanisms have been found to induce clinically relevant NK cell alloreactivity in transplantation, e.g., post-reconstitution functional reversal of anergic NK cells. More recently, activating KIR came into the spotlight for their potential ability to directly activate donor NK cells through in vivo recognition of HLA or other ligands. Novel therapeutic monoclonal antibodies (mAb) may optimize NK-mediated effects. Examples include obinutuzumab (GA101), a glyco-engineered anti-CD20 mAb with increased affinity for the FcγRIIIA receptor, enhancing antibody-dependent cellular cytotoxicity; lirilumab (IPH2102), a first-in-class NK-specific checkpoint inhibitor, blocking the interaction between the major KIR and cognate HLA-C antigens; and elotuzumab (HuLuc63), a humanized monoclonal antibody specific for SLAMF7, whose anti-myeloma therapeutic effects are partly due to direct activation of SLAMF7-expressing NK cells. In addition to conventional antibodies, NK cell-targeted bispecific (BiKEs) and trispecific (TriKEs) killer engagers have also been developed. These proteins elicit potent effector functions by binding target ligands (e.g., CD19, CD22, CD30, CD133, HLA class II, EGFR) on one arm and NK receptors on the other. An additional innovative approach to direct NK cell activity is genetic reprogramming with chimeric antigen receptors (CAR). To date, primary NK cells and the NK92 cell line have been engineered with CAR specific for antigens expressed on multiple tumors. Encouraging preclinical results warrant further development of this approach. This Research Topic welcomes contributions addressing mechanisms of NK-mediated activation in response to disease as well as past and contemporary strategies to enhance NK mediated reactivity through control of the interactions between NK receptors and their ligands.

Chimeric antigen receptors --- Checkpoint inhibitors --- NK receptors --- Immunotherapy --- Transplantation --- Natural killer cells --- Immune evasion --- Cancer --- Bispecific antibodies --- Chimeric antigen receptors --- Checkpoint inhibitors --- NK receptors --- Immunotherapy --- Transplantation --- Natural killer cells --- Immune evasion --- Cancer --- Bispecific antibodies

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Recognition and killing of aberrant, infected or tumor targets by Natural Killer (NK) cells is mediated by positive signals transduced by activating receptors upon engagement of ligands on target surface. These stimulatory pathways are counterbalanced by inhibitory receptors that raise NK cell activation threshold through negative antagonist signals. While regulatory effects are necessary for physiologic control of autoimmune aggression, they may restrain the ability of NK cells to activate against disease. Overcoming this barrier to immune surveillance, multiple approaches to enhance NK-mediated responses are being investigated since two decades. Propelled by considerable advances in the understanding of NK cell biology, these studies are critical for effective translation of NK-based immunotherapy principles into the clinic. In humans, dominant inhibitory signals are transduced by Killer Immunoglobulin Like Receptors (KIR) recognizing cognate HLA class I on target cells. Conversely, KIR recognition of “missing self-HLA” - due to HLA loss or HLA/ KIR mismatch - triggers NK-mediated tumor rejection. Initially observed in murine transplant models, these antitumor effects were later found to have important implications for the clinical outcome of haplotype-mismatched stemcell transplantation. Here, donor NK subsets protect against acute myeloid leukemia (AML) relapse through missing self recognition of donor HLA-C allele groups (C1 or C2) and/or Bw4 epitope. These studies were subsequently extended by trials investigating the antileukemia effects of adoptively transferred haplotype-mismatched NK cells in non-transplant settings. Other mechanisms have been found to induce clinically relevant NK cell alloreactivity in transplantation, e.g., post-reconstitution functional reversal of anergic NK cells. More recently, activating KIR came into the spotlight for their potential ability to directly activate donor NK cells through in vivo recognition of HLA or other ligands. Novel therapeutic monoclonal antibodies (mAb) may optimize NK-mediated effects. Examples include obinutuzumab (GA101), a glyco-engineered anti-CD20 mAb with increased affinity for the FcγRIIIA receptor, enhancing antibody-dependent cellular cytotoxicity; lirilumab (IPH2102), a first-in-class NK-specific checkpoint inhibitor, blocking the interaction between the major KIR and cognate HLA-C antigens; and elotuzumab (HuLuc63), a humanized monoclonal antibody specific for SLAMF7, whose anti-myeloma therapeutic effects are partly due to direct activation of SLAMF7-expressing NK cells. In addition to conventional antibodies, NK cell-targeted bispecific (BiKEs) and trispecific (TriKEs) killer engagers have also been developed. These proteins elicit potent effector functions by binding target ligands (e.g., CD19, CD22, CD30, CD133, HLA class II, EGFR) on one arm and NK receptors on the other. An additional innovative approach to direct NK cell activity is genetic reprogramming with chimeric antigen receptors (CAR). To date, primary NK cells and the NK92 cell line have been engineered with CAR specific for antigens expressed on multiple tumors. Encouraging preclinical results warrant further development of this approach. This Research Topic welcomes contributions addressing mechanisms of NK-mediated activation in response to disease as well as past and contemporary strategies to enhance NK mediated reactivity through control of the interactions between NK receptors and their ligands.

Chimeric antigen receptors --- Checkpoint inhibitors --- NK receptors --- Immunotherapy --- Transplantation --- Natural killer cells --- Immune evasion --- Cancer --- Bispecific antibodies

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Topics Covered Include: X-ray crystallography of ligands. Catalytic antibodies. Nature of the antigen. Antibody binding sites. Maturation of the immune response. Computational biochemistry of antibodies and T-cell receptors. Antigen-specific T-cell receptors and their reactions.Key Features* X-Ray Crystallography of Ligands* Catalytic Antibodies* Nature of the Antigen* Antibody Binding Sites* Maturtion of the Immune Response* Computational Biochemistry of Antibodies and * T-Cell Receptors* Antigen-Speci

Antigen-antibody reactions. --- T cells --- T cell receptors --- T lymphocyte antigen receptors --- Cell receptors --- Antibody-antigen reactions --- Antigens --- Immune response --- Immunoglobulins --- Immunology --- Receptors.

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The vertebrate immune system defends the organism against invading pathogens while at the same time being self-tolerant to the body’s own constituents thus preserving its integrity. Multiple mechanisms work in concert to ensure self-tolerance. Apart from purging the T cell repertoire from auto-reactive T cells via negative selection in the thymus dominant tolerance exerted by regulatory T cells plays a major role in tolerance imposition and maintenance. Among the various regulatory/suppressive cells hitherto described, CD4+CD25+ regulatory T cells (Treg) and interleukin-10 producing T regulatory 1 (Tr1) cells have been studied in most detail and are the subject of most articles in this issue. Treg, also called "natural" regulatory T cells, will be traced from their intra-thymic origin to the site of their action in peripheral lymphoid organs and tissues. The repertoire of Treg is clearly biased towards recognition of self-antigens, thereby potentially preventing autoimmune diseases such as gastritis and oophoritis. Regulatory T cells, however also control infections, allergies and tolerance to transplanted tissues and this requires their induction in the periphery under conditions which are not yet fully understood. The concept of dominant tolerance, by far not novel, will offer new insights and hopefully tools for the successful treatment of autoimmune diseases, improved cancer immunotherapy and transplant survival. The fulfillment of these high expectations will, however, require their unambiguous identification and a better understanding of their mode of action.

T cells. --- T cells --- CD4 antigen. --- CD25 antigen. --- Receptors. --- CD4 molecule --- CD4 receptors --- CD antigens --- Viruses --- T cell receptors --- T lymphocyte antigen receptors --- Cell receptors --- T lymphocytes --- Thymus-dependent cells --- Thymus-dependent lymphocytes --- Thymus-derived cells --- Lymphocytes --- Receptors --- Immunology. --- Immunobiology --- Life sciences --- Serology

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T cells --- Tumor antigens. --- Receptors, Chimeric Antigen --- Neoplasms --- Immunotherapy, Adoptive. --- Receptors, Antigen, T-Cell. --- Cell- and Tissue-Based Therapy. --- Receptors. --- therapeutic use. --- therapy. --- Therapy, Cell --- Therapy, Tissue --- Cell Therapy --- Tissue Therapy --- Cell and Tissue Based Therapy --- Tissue Therapy, Historical --- Receptors, T-Cell Antigen --- T-Cell Antigen Receptor --- T-Cell Receptor --- Antigen Receptors, T-Cell --- T-Cell Receptors --- Antigen Receptor, T-Cell --- Antigen Receptors, T Cell --- Receptor, T-Cell --- Receptor, T-Cell Antigen --- Receptors, T Cell Antigen --- Receptors, T-Cell --- T Cell Antigen Receptor --- T Cell Receptor --- T Cell Receptors --- T-Cell Antigen Receptors --- CD3 Complex --- Genes, T-Cell Receptor --- Complementarity Determining Regions --- Adoptive Immunotherapy --- CAR T-Cell Therapy --- Cellular Immunotherapy, Adoptive --- Chimeric Antigen Receptor Therapy --- Immunotherapy, Adoptive Cellular --- Adoptive Cellular Immunotherapy --- Adoptive Cellular Immunotherapies --- Adoptive Immunotherapies --- CAR T Cell Therapy --- CAR T-Cell Therapies --- Cellular Immunotherapies, Adoptive --- Immunotherapies, Adoptive --- Immunotherapies, Adoptive Cellular --- T-Cell Therapies, CAR --- T-Cell Therapy, CAR --- Therapies, CAR T-Cell --- Therapy, CAR T-Cell --- Killer Cells, Lymphokine-Activated --- Cytapheresis --- Lymphocytes, Tumor-Infiltrating --- Monocytes, Activated Killer --- Antigens --- Tumor markers --- T cell receptors --- T lymphocyte antigen receptors --- Cell receptors