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Efficient discrimination between different densities of target antigen by tetracycline-regulatable T bodies
L Alvarez-Vallina1, S J Russell
1Centre for Protein Engineering, MRC Centre, Cambridge, UK. lav@inmuno.cph.es
Abstract:
Engineered T cells expressing chimeric T cell receptors (chTCRs) are of interest for cancer gene therapy but many "cancer antigens" are thought to be unsuitable targets because they are expressed at low levels on normal tissues. We therefore sought to determine whether engineered T cells expressing variable surface densities of a high-affinity chTCR could discriminate different concentrations of the targeted antigen. We plotted the relationship between chTCR density and the concentration of target antigen using Jurkat T cells expressing a hapten-binding chTCR whose expression could be modulated by tetracycline. Our analysis reveals that there is a dynamic equilibrium between cell surface density of the chTCR and the antigen density that optimally triggers T cell activation. At a fixed density of target antigen, optimal T cell activation can be achieved only within a certain range of chTCR densities, while excessive TCR signaling triggers apoptosis of the engineered T cells. Our results show that T cells can be engineered to discriminate different antigen densities and that the T cell response to a fixed concentration of antigen can be optimized by tuning the cell surface density of TCRs.
Insights
Engineered T cells can distinguish varying cancer antigen levels by adjusting chimeric T cell receptor (chTCR) density. Optimizing chTCR levels enhances T cell activation and avoids self-destruction, crucial for cancer gene therapy.
Area of Science:
- Immunology
- Cancer Gene Therapy
- Cellular Engineering
Background:
- Chimeric T cell receptors (chTCRs) are promising for cancer gene therapy.
- Many cancer antigens are expressed at low levels on normal tissues, posing targeting challenges.
- Understanding T cell response to varying antigen densities is critical for therapeutic efficacy.
Purpose of the Study:
- To investigate if engineered T cells can discriminate between different target antigen concentrations.
- To determine the relationship between chTCR surface density and antigen concentration for optimal T cell activation.
- To explore the impact of excessive chTCR signaling on engineered T cell viability.
Main Methods:
- Utilized Jurkat T cells engineered to express a hapten-binding chTCR with tunable surface expression via tetracycline.
- Quantified the relationship between chTCR density and target antigen concentration.
- Analyzed T cell activation and apoptosis in response to varying antigen and chTCR densities.
Main Results:
- A dynamic equilibrium exists between chTCR density and antigen density for optimal T cell activation.
- Specific ranges of chTCR densities are required for effective T cell activation at fixed antigen densities.
- Excessive chTCR signaling leads to apoptosis of engineered T cells.
Conclusions:
- Engineered T cells can be designed to differentiate between varying antigen densities.
- Tuning chTCR surface density is a viable strategy to optimize T cell responses to specific antigen concentrations.
- This finding has significant implications for refining cancer gene therapy approaches.