Humanized TCR Mice With Host Constant Regions for T Cell Development
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Solution Overview
Problem
There is a need for non-human animals, such as rodents, capable of expressing human T cell receptor variable regions that can rearrange to form genes encoding fully human T cell receptor domains, and generate a diverse repertoire of human T cell receptor sequences for therapeutic applications, while avoiding immune responses against these receptors.
Innovation Solution
Genetically modified rodents are created with unrearranged human TCR variable gene loci, such as TCRα and TCRβ, linked to non-human constant gene sequences, allowing for the expression of human T cell receptors on their surface, enabling T cell development and generation of central and effector memory T cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If human TCR variable gene loci are introduced into non-human animals, then the ability to generate diverse human TCR repertoire is improved, but immune responses against the introduced receptors may occur
Solution Approach 1:
The patent introduces human TCR variable gene loci specifically at the endogenous TCR loci of non-human animals, replacing only the variable region segments while maintaining the constant regions and regulatory elements native to the host organism. This localized humanization approach ensures that the diverse human TCR repertoire is generated through V(D)J recombination of human variable segments, while the host's immune system recognizes the overall structure as self, thereby avoiding immune rejection.
2Ease of operation
If human TCR variable gene loci are linked to non-human constant gene sequences, then T cell development is enabled, but the TCR may not function optimally
Solution Approach 1:
The patent strategically combines human TCR variable gene segments with non-human constant gene sequences at the TCR loci. The human variable regions provide the necessary diversity and antigen recognition capability, while the non-human constant regions ensure proper folding, stability, and interaction with host MHC molecules and signaling components. This chimeric arrangement enables functional T cell development while maintaining optimal TCR performance in the non-human host system.
Data Source
AI summary
The invention provides a genetically modified non-human animal that comprises in its genome unrearranged T cell receptor variable gene loci, as well as embryos, cells, and tissues comprising the same. Also provided are constructs for making said genetically modified non-human animal and methods of making the same. Various methods of using the genetically modified non-human animal are also provided.