Abstract
The neonatal thymus generates Foxp3(+) regulatory T (tT(reg)) cells that are critical in controlling immune homeostasis and preventing multiorgan autoimmunity. The role of antigen specificity on neonatal tT(reg) cell selection is unresolved. Here we identify 17 self-peptides recognized by neonatal tT(reg) cells, and reveal ligand specificity patterns that include self-antigens presented in an age- and inflammation-dependent manner. Fate-mapping studies of neonatal peptidyl arginine deiminase type IV (Padi4)-specific thymocytes reveal disparate fate choices. Neonatal thymocytes expressing T cell receptors that engage IA(b)-Padi4 with moderate dwell times within a conventional docking orientation are exported as tT(reg) cells. In contrast, Padi4-specific T cell receptors with short dwell times are expressed on CD4(+) T cells, while long dwell times induce negative selection. Temporally, Padi4-specific thymocytes are subject to a developmental stage-specific change in negative selection, which precludes tT(reg) cell development. Thus, a temporal switch in negative selection and ligand binding kinetics constrains the neonatal tT(reg) selection window.