B6-hFCGR1 Mice

Catalog Number: C001500

Genetic Background: C57BL/6NCya

Reproduction: Homozygote x Homozygote

Strain Description

FCGR1 gene encodes FcγRI, a specific receptor for IgG antibodies, also known as CD64. This receptor plays a key role in human immune responses. FcγRI has a high affinity for the Fc portion of IgG antibodies and is the only member of the human FcγRs with a high affinity for monomeric IgG. It plays important roles in both innate and adaptive immune responses ^[1]. FcγRI is expressed on a variety of immune cells, including monocytes, macrophages, dendritic cells, and neutrophils. It plays a critical role in host defense against infection and humoral immunity by influencing processes such as phagocytosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and antigen presentation ^[2-3]. The binding of FcγRI to IgG-coated target cells promotes their phagocytosis by immune cells. This is an important mechanism for clearing infected cells, apoptotic cells, and other foreign particles. In addition, this binding can also promote the release of cytotoxic granules by immune cells, such as natural killer cells and cytotoxic T cells, leading to the killing and lysis of target cells. In antigen presentation, FcγRI binding to IgG-coated antigens promotes dendritic cells to take them up and present them to T cells, which is essential for the initiation of adaptive immune responses. In addition, FcγRI is involved in a variety of important physiological processes, such as wound healing and inflammation. FcγRI plays a critical role in antibody-based immunotherapy, which has important implications for the development of therapeutic drugs and methods for a variety of autoimmune diseases, infectious diseases, and tumors ^[4-5].

This model represents a humanized FCGR1 mouse, generated by substituting the mouse Fcgr1 gene sequence (inclusive of the UTR) with the corresponding human FCGR1 gene sequence. This modification enables the expression of human FcγRI in mice. Homozygous B6-hFCGR1 mice exclusively express human FcγRI receptors, with the proportion of cells expressing human FcγRI mirroring that of cells expressing mouse FcγRI in wild-type mice. Consequently, this model serves as a valuable tool for various research areas, including the evaluation of human IgG antibody affinity, exploration of the ADCC mechanism, investigation into immune cell phagocytosis and antigen presentation. Furthermore, it provides a platform for the preclinical assessment of therapeutic human IgG antibodies.

Strain Strategy

The mouse Fcgr1 gene sequence (from about 5 kb upstream of the Fcgr1 gene to about 3 kb downstream of the Fcgr1 gene) was completely replaced with the corresponding sequence in the human FCGR1A gene (from about 7 kb upstream of the FCGR1A gene to about 3 kb downstream of the FCGR1A gene) by gene editing technology.

Validation Data

1. Successful expression of human FcγRI by splenic immune cells

Figure 1. Expression of human FcγRI protein (hFcγRI) and mouse FcγRI protein (mFcγRI) in various immune cell lineages in the spleen. FcγRI types expressed in splenic myeloid cells (Cd11b+), bone marrow-derived dendritic cells (Cd11b+Cd11c+ BMDC), NK cells, and T cells of wild-type mice (C57BL/6N) and B6-hFCGR1 mice, respectively, were detected by flow cytometry using the species-specific FcγRI antibodies. The assay results showed that FcγRI in the spleen of wild-type mice was mainly expressed in myeloid cells and BMDC, less in NK cells, and almost not in T cells. While B6-hFCGR1 mice successfully expressed human FcγRI protein (hFcγRI) and hardly expressed mouse FcγRI protein (mFcγRI), and the proportion of human FcγRI-expressing cells was comparable to that of mouse FcγRI-expressing cells in wild-type mice.

 

2. Detection of mouse Calcrl gene expression

Figure 2. Expression of human FcγRI protein (hFcγRI) and mouse FcγRI protein (mFcγRI) in various immune cell lineages in peripheral blood (PB). The types of FcγRI expressed in peripheral blood myeloid lineage cells (Cd11b+), bone marrow-derived dendritic cells (Cd11b+Cd11c+ BMDC), NK cells and T cells were detected by flow cytometry in wild-type (C57BL/6N) and B6-hFCGR1 mice, respectively, using the species-specific FcγRI antibodies. The assay results showed that FcγRI in the peripheral blood of wild-type mice was mainly expressed in myeloid cells and BMDC, less in NK cells, and almost not in T cells. While B6-hFCGR1 mice successfully expressed human FcγRI protein (hFcγRI) and hardly expressed mouse FcγRI protein (mFcγRI), and the proportion of human FcγRI-expressing cells was comparable to that of mouse FcγRI-expressing cells in wild-type mice.

Reference

[1] van der Poel CE, Spaapen RM, van de Winkel JG, Leusen JH. Functional characteristics of the high affinity IgG receptor, FcγRI. J Immunol. 2011 Mar 1;186(5):2699-704.

[2] Lu J, Chu J, Zou Z, Hamacher NB, Rixon MW, Sun PD. Structure of FcγRI in complex with Fc reveals the importance of glycan recognition for high-affinity IgG binding. Proc Natl Acad Sci U S A. 2015 Jan 20;112(3):833-8.

[3] Junker F, Gordon J, Qureshi O. Fc Gamma Receptors and Their Role in Antigen Uptake, Presentation, and T Cell Activation. Front Immunol. 2020 Jul 3;11:1393.

[4] Hogarth PM, Pietersz GA. Fc receptor-targeted therapies for the treatment of inflammation, cancer and beyond. Nat Rev Drug Discov. 2012 Mar 30;11(4):311-31.

[5] Holtrop T, Budding K, Brandsma AM, Leusen JHW. Targeting the high affinity receptor, FcγRI, in autoimmune disease, neuropathy, and cancer. Immunother Adv. 2022 May 28;2(1):ltac011.