Thymocyte Development of Humanized Mice Is Promoted by Interactions with Human-Derived Antigen Presenting Cells upon...

Area of Science:

• Immunology
• Transplantation Biology
• Mice Models

Background:

• Humanized mice are crucial for studying human immunity but often show inefficient responses.
• Previous work established intra-bone marrow injection of CD133+ cord blood cells into immunodeficient mice (IBMI-huNSG) for immune responses against HTLV-1.
• Mechanisms underlying immune responses in IBMI-huNSG mice remained unclear.

Purpose of the Study:

• To investigate thymocyte development in IBMI-huNSG mice.
• To elucidate the roles of human and mouse MHC restriction in immune responses.
• To understand the mechanisms of enhanced immune responses post-immunization.

Main Methods:

• Generation of IBMI-huNSG mice via intra-bone marrow injection.
• Analysis of thymocyte development and thymic structures.
• Immunization of mice and subsequent analysis of thymic and peripheral immune cells.
• Organ culture of thymus with neutralizing antibodies.
• Live imaging of thymic cellular interactions and signaling pathway activation (Rap1).

Main Results:

• IBMI-huNSG mice exhibited normal developmental profiles but aberrant thymic structures.
• Immunization led to expanded thymic medulla-like regions with increased HLA-DR+ cells, including CD205+ dendritic cells (DCs).
• HLA-DR-dependent expansion of CD4 single positive thymocytes was observed.
• Mature peripheral T-cells showed alloreactive proliferation.
• Live imaging revealed dynamic thymocyte-DC interactions with Rap1 activation.

Conclusions:

• Increased HLA-DR+ cells post-immunization promote HLA-restricted thymocyte expansion in humanized mice.
• This study elucidates mechanisms of enhanced immune responses in IBMI-huNSG mice.
• The findings offer a simplified method for generating humanized mice with improved immune function.