PRECISE-seq reveals disease-relevant TCR repertoires with phenotypic plasticity

Area of Science:

• Immunology
• Molecular Biology
• Cancer Research

Background:

• Understanding T cell phenotypes, antigen specificity, and functional avidity is crucial for immune responses in infection and cancer.
• Existing methods lack the resolution to link these factors at a single-cell level.

Purpose of the Study:

• To develop a novel method, PRECISE-seq, for high-resolution T cell analysis.
• To link T cell receptor (TCR) avidity with T cell phenotypes in disease contexts.

Main Methods:

• PRECISE-seq integrates multi-omics T cell analysis with proximity labeling.
• The method enables rapid screening of disease-relevant T cell repertoires.
• Quantitative measurement of functional avidity in physiological contexts.

Main Results:

• PRECISE-seq accurately identified CMV-specific T cell clonotypes and measured functional avidity.
• High-potency CMV-specific T cells exhibited an exhausted phenotype.
• Tumor-reactive CD8+ T cells differentiated into a protumor Ly49+ regulatory state (TLy49), distinct from exhaustion.
• PD-1 blockade reduced TLy49 formation and promoted effector T cell revival, correlating with immunotherapy response.

Conclusions:

• PRECISE-seq provides high-resolution mapping of TCR potency and T cell phenotype.
• A novel regulatory axis shapes T cell fate in tumors.
• Understanding T cell states is critical for predicting and improving immunotherapy outcomes.