Document Type
Article
Publication Date
10-12-2024
Original Citation
Darguzyte M,
Antczak P,
Bachurski D,
Hoelker P,
Abedpour N,
Gholamipoorfard R,
Schlößer H,
Wennhold K,
Thelen M,
Garcia-Marquez M,
Koenig J,
Schneider A,
Braun T,
Klawonn F,
Damrat M,
Rahman M,
Kleid J,
Theobald S,
Bauer E,
von Kaisenberg C,
Talbot S,
Shultz LD,
Soper B,
Stripecke R.
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. Cells. 2024;13(20):1686.
Keywords
JMG, Animals, Humans, Mice, T-Lymphocytes, Immune Reconstitution, Mice, Inbred NOD, Mice, SCID, Major Histocompatibility Complex, Hematopoietic Stem Cell Transplantation, Mice, Knockout, Hematopoietic Stem Cells, Hematopoiesis, Transcriptome
JAX Source
Cells. 2024;13(20):1686.
ISSN
2073-4409
PMID
39451205
DOI
https://doi.org/10.3390/cells13201686
Grant
This work was supported by The Jackson Laboratory (Grant LV-HLA) as an academic collaboration contracted grant (to R.S.).the Juvenile Diabetes Research Foundation (JDRF-5-COE-2020-967-M-N-02) (to L.S.).
Abstract
Background: Humanized mice transplanted with CD34+ 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: Human immune reconstitution was detectable in peripheral blood from 8 to 20 weeks after the transplantation of NSG-DKO. Human single positive CD4+ and CD8+ 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.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.