Selective ablation of thymic and peripheral Foxp3⁺ regulatory T cell development

Area of Science:

• Immunology
• Cell Biology

Background:

• Foxp3+ regulatory T (Treg) cells, originating from the thymus (tTreg) and periphery (pTreg), are crucial for immune homeostasis.
• Self-reactive tTreg cells are thought to primarily control autoimmune responses.

Purpose of the Study:

• To investigate the functional adaptability and compensatory roles of tTreg and pTreg cells.
• To understand the impact of selectively ablating tTreg or pTreg cells on immune tolerance and autoimmunity.

Main Methods:

• Utilized a Foxp3-dependent reporter with thymus-specific GFP/Cre activity for selective ablation of tTreg or pTreg cells.
• Compared Treg cell function and immune tolerance in C57BL/6 and autoimmune-prone NOD mouse models.
• Conducted genetic association studies to identify autoimmune risk loci.

Main Results:

• pTreg cells compensated for the absence of tTreg cells in C57BL/6 mice, maintaining immune tolerance and preventing mortality.
• In autoimmune-prone NOD mice, the absence of tTreg cells led to severe disease lethality and early-onset autoimmune diabetes, abrogating the typical sex bias.
• Identified key autoimmune risk loci influencing Treg cell biology and beta cell autoimmunity.

Conclusions:

• Peripheral-derived Treg cells exhibit significant functional adaptability and can compensate for thymic-derived Treg cell deficiencies.
• The compensatory capacity of pTreg cells is insufficient to prevent severe autoimmunity in genetically susceptible individuals.
• These findings underscore the critical role of pTreg cells in mediating bystander effects for self-tolerance.