Antigen-Specific Regulatory T Cells via Endogenous TCR Extraction
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Solution Overview
Problem
Current methods for manufacturing regulatory T cells (Tregs) specific to desired antigens are inefficient, leading to nonspecific immunosuppression and inadequate efficacy in treating autoimmune diseases and transplant-related conditions.
Innovation Solution
The method involves identifying and introducing a T cell receptor (TCR) with high antigen binding capability from effector T cells into regulatory T cells by deleting the endogenous TCR and expressing the identified TCR pair, ensuring antigen specificity and regulated immunosuppression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional Tregs with endogenous TCR are used for immunosuppression, then immunosuppressive action is achieved, but antigen nonspecific suppression occurs leading to excessive suppression of normal immune responses
Solution Approach 1:
The patent extracts and removes the endogenous TCR from regulatory T cells, then introduces a specific exogenous TCR. This extraction of the problematic endogenous TCR allows the Treg to lose its nonspecific immunosuppressive action while gaining antigen-specific suppression capability through the introduced TCR.
Solution Approach 2:
The patent confers antigen-specific quality to the Treg by introducing a TCR that recognizes a specific antigen. This creates local quality where the immunosuppression is targeted specifically to antigen-positive cells rather than being a general property of all Tregs, thereby achieving selective immunosuppression.
2Adaptability or versatility
If TCR is introduced into Treg to achieve antigen specificity, then antigen-specific immunosuppression is achieved, but endogenous TCR interference and mispairing occur
Solution Approach 1:
The patent removes the endogenous TCR from the Treg before introducing the exogenous TCR. This extraction eliminates the source of interference and mispairing problems, ensuring that only the intended exogenous TCR is expressed in the Treg, thereby stabilizing TCR expression and improving reliability.
Solution Approach 2:
The patent performs preliminary removal of endogenous TCR genes before introducing the exogenous TCR. This preliminary action prevents potential interference and mispairing issues that would arise if both endogenous and exogenous TCRs were present simultaneously, ensuring clean and stable TCR expression.
3Adaptability or versatility
If TCR gene is introduced into Treg, then antigen-specific Treg is produced, but manufacturing complexity increases
Solution Approach 1:
The patent simplifies the manufacturing process by completely removing endogenous TCR genes before introducing the exogenous TCR. This extraction approach avoids the complexity of managing dual TCR systems and simplifies quality control, as the final product contains only the desired specific TCR without endogenous TCR interference.
Data Source
AI summary
The present disclosure provides a technique for producing regulatory T cells specific to a desired antigen. Regulatory T cells specific to an antigen are produced by a method that includes: a step for identifying a T cell receptor (TCR) clone present in an effector T cell population specific to an antigen in an effector T cell donor; and a step for introducing all or part of the nucleic acid sequence of the TCRα gene and all or part of the nucleic acid sequence of the TCRβ gene included in the clone into a regulatory T cell, said step comprising introducing the TCRα and the TCRβ so as to be expressed in pairs.