Long-Term Human Immune Reconstitution, T-Cell Development, and Immune Reactivity in Mice Lacking the Murine Major Histocompatibility Complex: Validation with Cellular and Gene Expression Profiles
Year: 2024
Type: article
Abstract: BACKGROUND: hematopoietic cells (HPCs) are broadly used to study human immune responses and infections in vivo and for testing therapies pre-clinically. However, until now, it was not clear whether interactions between the mouse major histocompatibility complexes (MHCs) and/or the human leukocyte antigens (HLAs) were necessary for human T-cell development and immune reactivity. METHODS: We evaluated the long-term (20-week) human hematopoiesis and human T-cell development in NOD Scid Gamma (NSG) mice lacking the expression of MHC class I and II (NSG-DKO). Triplicate experiments were performed with HPCs obtained from three donors, and humanization was confirmed in the reference strain NOD Rag Gamma (NRG). Further, we tested whether humanized NSG-DKO mice would respond to a lentiviral vector (LV) systemic delivery of HLA-A*02:01, HLA-DRB1*04:01, human GM-CSF/IFN-α, and the human cytomegalovirus gB antigen. RESULTS: T-cells were detectable in lymphatic tissues (thymus, bone marrow, and spleen). LV delivery harnessed the detection of lymphocyte subsets in bone marrow (αβ and γδ T-cells and NK cells) and the expression of HLA-DR. Furthermore, RNA sequencing showed that LV delivery increased the expression of different human reactome pathways, such as defense responses to other organisms and viruses. CONCLUSIONS: Human T-cell development and reactivity are independent of the expression of murine MHCs in humanized mice. Therefore, humanized NSG-DKO is a promising new model for studying human immune responses, as it abrogates the xenograft mouse MHC interference.
Source: Cells
Authors: Milita Darguzyte, Philipp Antczak, Daniel Bachurski, Patrick Hoelker, Nima Abedpour, Rahil Gholamipoorfard, Hans A. Schlößer, Kerstin Wennhold, Martin Thelen, Maria A. Garcia-Marquez, Johannes Koenig, Andreas Schneider, Tobias Braun, Frank Klawonn, Michael Damrat, Masudur Rahman, Jan-Malte Kleid, Sebastian J. Theobald, Eugen Bauer, Constantin von Kaisenberg, Steven R. Talbot, Leonard D. Shultz, Brian Soper, Renata Stripecke
Institutions: University of Cologne, University Hospital Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, Medizinische Hochschule Hannover, Ostfalia University of Applied Sciences, Helmholtz Centre for Infection Research, German Center for Infection Research, Jackson Laboratory
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,069
Funders: Jackson Laboratory, Juvenile Diabetes Research Foundation United States of America, Deutsches Zentrum für Infektionsforschung, Deutsche Forschungsgemeinschaft, Medizinischen Hochschule Hannover, Deutsche Krebshilfe, Universität zu Köln, Center for Molecular Medicine Cologne, University of Cologne
Awards: G1258522988, G2358456658, G2429433263, G2588026138, Tumorprogression und Therapieresistenz in KopfHalsPlattenepithelkarzinomen, G3486220055, West German Genome Center, G3816707072, G410615943, G4163493018, G4524544361, G4711780682, G4779636751, G5145181653, G5416425412, G5496285032, G5602640301, G5816769565, G618086180, G6238744110, G6289279129, Zentrale Koordinationseinheit des Next Generation Sequencing Kompetenznetzwerks, G6729321963, SFB 1530: Aufklärung und Targeting pathogener Mechanismen bei BZellNeoplasien, G6957823684, G6977693643, G7360399907, G7366101143, G7519569422, G7550356875, G7773928716, G8011138159, G8027973120, G8179878042, G874258834
OpenAlex ID: W4403401746