Humanization of T cell-mediated immunity in mice

Area of Science:

• Immunology
• Genetics
• Biotechnology

Background:

• Studying human T cell receptors (TCRs) with specific functions is difficult, hindering T cell therapy development.
• Existing models do not fully recapitulate human T cell responses for therapeutic discovery.

Purpose of the Study:

• To develop a genetically humanized mouse model for studying human T cell immunity and discovering therapeutic TCRs.
• To overcome limitations in isolating and analyzing human TCRs of defined specificity.

Main Methods:

• Utilized VelociGene technology to replace murine TCRαβ variable regions and co-receptor/MHC genes with human sequences, creating VelociT mice.
• Assessed immune cell populations, TCR repertoire diversity, and T cell responses to viral infection and autoimmune models.
• Immunized VelociT mice with tumor antigens to identify and characterize novel therapeutic TCRs.

Main Results:

• VelociT mice exhibit normal immune cell populations and diverse TCR repertoires, comparable to wild-type mice.
• Demonstrated functional T cell responses to viral infections (LCMV) and development of experimental autoimmune encephalomyelitis.
• Identified a human TCR targeting NYESO-1 with potent antitumor activity, showcasing the model's therapeutic potential.

Conclusions:

• VelociT mice provide a powerful, clinically relevant model for analyzing human T cell function in disease.
• This platform facilitates the discovery of novel therapeutic human TCRs for cancer immunotherapy and other diseases.