The Alternative NF-κB Pathway in Regulatory T Cell Homeostasis and Suppressive Function

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• CD4+Foxp3+ regulatory T cells (Tregs) are vital for immune homeostasis and preventing autoimmunity.
• Canonical NF-κB pathway components (c-Rel, p65) are known to be crucial for Treg function.
• The role of alternative NF-κB pathway components (p100, RelB) in Tregs is largely unknown.

Purpose of the Study:

• To investigate the function of the alternative NF-κB pathway, specifically p100 and RelB, in CD4+Foxp3+ regulatory T cells (Tregs).
• To elucidate the molecular mechanisms underlying Treg homeostasis and immune tolerance involving the alternative NF-κB pathway.

Main Methods:

• Conditional gene deletion of nfkb2 (encoding p100) and relb in Tregs using mouse models.
• Assessment of Treg suppressive function and inflammatory phenotypes in knockout mice.
• Comparative analysis of single and double knockout models for nfkb2 and relb.

Main Results:

• Conditional deletion of nfkb2 in Tregs led to severe inflammation due to impaired Treg suppressive function.
• Mice lacking RelB in Tregs did not show a similar inflammatory phenotype.
• Simultaneous deletion of both relb and nfkb2 in Tregs rescued the inflammatory phenotype observed in nfkb2-deficient Tregs.

Conclusions:

• p100 acts as an inhibitor of RelB in CD4+Foxp3+ regulatory T cells (Tregs).
• The alternative NF-κB pathway plays a critical, previously unrecognized role in Treg biology.
• These findings offer new insights into molecular pathways regulating immune tolerance and immunity.