Nikzad et al. generated humanized BLT (BM, liver, thymus) mice with a functional human donor-matched immune system. Human NK cells from the livers of BLT mice responded to vaccination (consisting of syngeneic DCs loaded with the HIV envelope protein) by altering the expression of activating and inhibitory receptors, adhesion molecules, and effector molecules in vivo and killing their target cells in vitro in an antigen-specific manner. Skin injection of varicella zoster virus in human volunteers with a history of chickenpox detected decades-long, antigen-specific immunological memory in tissue-resident human NK cells.
Adaptive immune responses are defined as antigen sensitization-dependent and antigen-specific responses leading to establishment of long-lived immunological memory. Although natural killer (NK) cells have traditionally been considered cells of the innate immune system, mounting evidence in mice and nonhuman primates warrants reconsideration of the existing paradigm that B and T cells are the sole mediators of adaptive immunity. However, it is currently unknown whether human NK cells can exhibit adaptive immune responses. We therefore tested whether human NK cells mediate adaptive immunity to virally encoded antigens using humanized mice and human volunteers. We found that human NK cells displayed vaccination-dependent, antigen-specific recall responses in vitro, when isolated from livers of humanized mice previously vaccinated with HIV-encoded envelope protein. Furthermore, we discovered that large numbers of cytotoxic NK cells with a tissue-resident phenotype were recruited to sites of varicella-zoster virus (VZV) skin test antigen challenge in VZV-experienced human volunteers. These NK-mediated recall responses in humans occurred decades after initial VZV exposure, demonstrating that NK memory in humans is long-lived. Our data demonstrate that human NK cells exhibit adaptive immune responses upon vaccination or infection. The existence of human memory NK cells may allow for the development of vaccination-based approaches capable of establishing potent NK-mediated memory functions contributing to host protection.
Author Info: (1) Center for Human Immunobiology, Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, USA. Translational Biology and Molecular Medici
Author Info: (1) Center for Human Immunobiology, Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, USA. Translational Biology and Molecular Medicine Graduate Program at Baylor College of Medicine, Houston, TX, USA. Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA, USA. (2) Center for Human Immunobiology, Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, USA. (3) Center for Human Immunobiology, Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, USA. Integrative Molecular and Biomedical Sciences Graduate Program at Baylor College of Medicine, Houston, TX, USA. (4) Center for Human Immunobiology, Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, USA. Graduate Program in Immunology at Baylor College of Medicine, Houston, TX, USA. (5) Center for Human Immunobiology, Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, USA. (6) Center for Human Immunobiology, Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, USA. Graduate Program in Immunology at Baylor College of Medicine, Houston, TX, USA. (7) Division of Infection and Immunity, University College London, UK. (8) Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. (9) Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. (10) Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. (11) Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA. (12) Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. Chan Zuckerberg Biohub, San Francisco, CA, USA. (13) Division of Infection and Immunity, University College London, UK. (14) Center for Human Immunobiology, Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, USA. paust@scripps.edu. Translational Biology and Molecular Medicine Graduate Program at Baylor College of Medicine, Houston, TX, USA. Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA, USA. Integrative Molecular and Biomedical Sciences Graduate Program at Baylor College of Medicine, Houston, TX, USA. Graduate Program in Immunology at Baylor College of Medicine, Houston, TX, USA.
