PDL1-Expressing Cells Convert Th1 to Regulatory T Cells
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Solution Overview
Problem
There is a need for compositions and methods to differentiate Th1 cells, as existing technologies do not effectively modulate Th1 cell plasticity, and the role of PD1/PDL1 interactions in this process remains unexplored.
Innovation Solution
A method involving contacting T cells with a K562 cell modified to express agents capable of activating PD1 signaling, such as PDL1, PDL2, or anti-PD1 antibodies, to convert Th1 cells into regulatory T cells, thereby promoting a regulatory phenotype and suppressing effector T cell activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Th1 cells are activated to protect against tumors and infections, then host protection is improved, but self-tolerance is compromised leading to autoimmune responses
Solution Approach 1:
The patent uses PDL1-expressing cells as an intermediary to modulate Th1 cell activity. The PDL1 ligand acts as a mediator that binds to PD1 on Th1 cells, delivering an inhibitory signal that converts activated Th1 cells into regulatory T cells, thereby reducing autoimmune responses while maintaining protective immunity
Solution Approach 2:
The patent changes the functional state of Th1 cells by activating PD1 signaling through PDL1 exposure. This parameter change transforms Th1 cells from a pro-inflammatory effector phenotype to a regulatory phenotype, altering their cytokine profile and suppressive function to prevent autoimmune pathology
2Object-affected harmful factors
If Th1 cells are tightly regulated to promote self-tolerance, then autoimmune responses are reduced, but protective immunity against tumors and infections is weakened
Solution Approach 1:
The patent applies preliminary regulation by exposing Th1 cells to PDL1-expressing cells before they encounter antigens in tumor or infection settings. This pre-conditioning converts Th1 cells into regulatory T cells that can then modulate subsequent immune responses, providing controlled protection without excessive autoimmunity
Solution Approach 2:
The patent introduces dynamic regulation where Th1 cells can switch between effector and regulatory phenotypes based on PDL1 signaling intensity and context. This dynamic plasticity allows the immune system to adapt Th1 cell function to different physiological conditions, maintaining protection while preventing autoimmunity
3Object-affected harmful factors
If PD1 signaling is activated to convert Th1 cells into regulatory T cells, then alloreactive T cell suppression is improved, but T cell receptor signaling is inhibited
Solution Approach 1:
The patent extracts the regulatory function from the T cell receptor signaling pathway by activating PD1 independently. PD1 signaling through PDL1 engagement provides a separate inhibitory pathway that converts Th1 cells into regulatory T cells without completely blocking TCR-mediated antigen recognition, allowing selective suppression of alloreactivity while preserving protective immunity
Data Source
AI summary
The present invention provides methods and compositions for converting a T cell into a cell that exhibits at least one regulatory T cell phenotype. The converted T cell is generated by contacting a T cell with a cell that is modified to comprise an agent capable of activating PD1 signaling in a T cell. The converted T cell is useful for preventing, suppressing, blocking or inhibiting an immune response. For example the converted T cell is useful for preventing rejection of a transplanted tissue in a human or other animal host, or protecting against graft versus host disease. The converted T cell can also be used to treat autoimmune diseases.