Transcript-indexed ATAC-seq for precision immune profiling.

Area of Science:

• Immunology
• Genomics
• Epigenetics

Background:

• T cells exhibit extensive T cell receptor (TCR) diversity for specific peptide-MHC ligand recognition.
• Understanding the interplay between TCR specificity and cellular epigenomic state is crucial for T cell function.

Purpose of the Study:

• To develop a single-cell method combining TCR sequencing with ATAC-seq for simultaneous analysis of TCR specificity and epigenomic state.
• To identify epigenomic signatures associated with T cell states and malignancies.

Main Methods:

• Developed and applied transcript-indexed ATAC-seq (T-ATAC-seq) at the single-cell level.
• Integrated TCR gene sequencing with ATAC-seq data from immortalized, primary healthy, and primary leukemic T cells.

Main Results:

• Identified cis and trans regulators of naive and memory CD4+ T cell states in healthy individuals.
• Revealed substantial heterogeneity within surface-marker-defined T cell populations.
• Differentiated leukemic and non-leukemic regulatory pathways in cutaneous T cell lymphoma patients by separating malignant clone signals from background noise.

Conclusions:

• T-ATAC-seq is a novel tool for analyzing epigenomic landscapes in clonal T cells.
• This method is valuable for studying T cell malignancy, immunity, and immunotherapy.
• The findings provide insights into T cell regulation and heterogeneity in health and disease.