Thymic regulatory T cells arise via two distinct developmental programs

Area of Science:

• Immunology
• Developmental Biology
• Cell Biology

Background:

• The generation of diverse regulatory T cell (Treg) repertoires capable of responding to self and non-self antigens is not fully understood.
• Regulatory T cells are critical for maintaining immune homeostasis and preventing autoimmunity.

Purpose of the Study:

• To elucidate the distinct developmental programs underlying the generation of mature regulatory T cell repertoires.
• To investigate the functional differences between Treg cell subsets originating from distinct developmental pathways.

Main Methods:

• Transcriptomic analysis
• Histocytometry
• Apoptosis assays
• T cell receptor repertoire analysis
• Experimental autoimmune encephalitis model

Main Results:

• Two distinct Treg cell progenitor populations, CD25+ TregP and Foxp3lo TregP cells, were identified.
• CD25+ TregP cells exhibited higher apoptosis rates and affinity for self-antigens, with distinct TCR repertoires and transcriptomes compared to Foxp3lo TregP cells.
• Distinct signaling pathways and enhancers regulated the development of each progenitor type, suggesting co-option of negative and positive selection programs.
• Treg cells derived from CD25+ TregP cells, but not Foxp3lo TregP cells, conferred protection against experimental autoimmune encephalitis.

Conclusions:

• Mature Treg cells are generated through at least two distinct developmental programs.
• Both developmental pathways are essential for a comprehensive Treg cell repertoire necessary for establishing immunotolerance.
• Understanding these distinct Treg cell developmental programs offers insights into potential therapeutic strategies for autoimmune diseases.