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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.

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.

Authors :
Darguzyte, Milita
Antczak, Philipp
Bachurski, Daniel
Hoelker, Patrick
Abedpour, Nima
Gholamipoorfard, Rahil
Schlößer, Hans A.
Wennhold, Kerstin
Thelen, Martin
Garcia-Marquez, Maria A.
Koenig, Johannes
Schneider, Andreas
Braun, Tobias
Klawonn, Frank
Damrat, Michael
Rahman, Masudur
Kleid, Jan-Malte
Theobald, Sebastian J.
Bauer, Eugen
von Kaisenberg, Constantin
Source :
Cells (2073-4409); Oct2024, Vol. 13 Issue 20, p1686, 27p
Publication Year :
2024

Abstract

Background: Humanized mice transplanted with CD34<superscript>+</superscript> 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<superscript>+</superscript> and CD8<superscript>+</superscript> 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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
20734409
Volume :
13
Issue :
20
Database :
Complementary Index
Journal :
Cells (2073-4409)
Publication Type :
Academic Journal
Accession number :
180555734
Full Text :
https://doi.org/10.3390/cells13201686