A temporal thymic selection switch and ligand binding kinetics constrain neonatal Foxp3⁺ T_reg cell development

Area of Science:

• Immunology
• Developmental Biology
• T cell biology

Background:

• Neonatal thymus generates Foxp3+ regulatory T (tTreg) cells crucial for immune homeostasis and preventing autoimmunity.
• The precise role of antigen specificity in neonatal tTreg cell selection remains unclear.

Purpose of the Study:

• To identify self-peptides recognized by neonatal tTreg cells.
• To investigate how antigen recognition and T cell receptor (TCR) interactions influence tTreg cell development.

Main Methods:

• Identification of 17 self-peptides recognized by neonatal tTreg cells.
• Fate-mapping studies of neonatal thymocytes specific for peptidyl arginine deiminase type IV (Padi4).
• Analysis of TCR dwell times and binding kinetics in relation to thymocyte selection.

Main Results:

• Discovered ligand specificity patterns for self-antigens, including age- and inflammation-dependent presentation.
• Demonstrated that moderate TCR dwell times favor export as tTreg cells, while short dwell times lead to CD4+ T cell development.
• Observed that long TCR dwell times induce negative selection, and a temporal switch in negative selection impacts tTreg development.

Conclusions:

• Neonatal tTreg cell selection is constrained by a temporal switch in negative selection and specific ligand binding kinetics.
• Antigen specificity, TCR dwell time, and developmental stage collectively regulate the neonatal tTreg cell selection window.