| Autor: |
Stadinski, Brian D., Blevins, Sydney J., Spidale, Nicholas A., Duke, Brian R., Huseby, Priya G., Stern, Lawrence J., Huseby, Eric S. |
| Zdroj: |
Nature Immunology; August 2019, Vol. 20 Issue: 8 p1046-1058, 13p |
| Abstrakt: |
The neonatal thymus generates Foxp3+regulatory T (tTreg) cells that are critical in controlling immune homeostasis and preventing multiorgan autoimmunity. The role of antigen specificity on neonatal tTregcell selection is unresolved. Here we identify 17 self-peptides recognized by neonatal tTregcells, 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 IAb-Padi4 with moderate dwell times within a conventional docking orientation are exported as tTregcells. 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 tTregcell development. Thus, a temporal switch in negative selection and ligand binding kinetics constrains the neonatal tTregselection window. |
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