Multimodal human thymic profiling reveals trajectories and cellular milieu for T agonist selection

Area of Science:

• Immunology
• Developmental Biology
• Cell Biology

Background:

• Self-reactive T cells are typically eliminated to prevent autoimmunity.
• Alternative fates, such as developing into tolerogenic T cell lineages, exist.
• Thymocyte development and selection are influenced by spatial context and cell interactions.

Purpose of the Study:

• To investigate the spatial and molecular mechanisms of alternative T cell development in the human thymus.
• To identify the cell types and signaling pathways involved in agonist selection of thymocytes.

Main Methods:

• Utilized Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) on human thymus samples.
• Employed spatial transcriptomics to analyze gene expression and cellular localization.
• Characterized thymocyte populations based on T cell receptor (TCR) signaling and lineage markers.

Main Results:

• Thymocytes with strong TCR signaling diverged from conventional development before CD4+ or CD8+ lineage commitment.
• Various agonist-selected T cell populations (e.g., CD8αα, T(agonist), Treg) showed distinct induction timings.
• Dendritic cells, B cells, and stromal cells were identified as key contributors to agonist selection through chemokines and co-stimulatory molecules.

Conclusions:

• Agonist selection provides an alternative fate for self-reactive thymocytes, leading to regulatory T cell populations.
• Specific spatial niches and cellular interactions within the thymus orchestrate this alternative developmental pathway.
• Understanding these mechanisms is crucial for harnessing the immunoregulatory potential of agonist-selected T cells in clinical applications.