Foxp3-expressing regulatory T (Treg) cells are essential for immune tolerance; 
however, the molecular mechanisms underlying Treg cell expansion and function 
are still not well understood. SUMOylation is a protein post-translational 
modification characterized by covalent attachment of SUMO moieties to lysines. 
UBC9 is the only E2 conjugating enzyme involved in this process, and loss of 
UBC9 completely abolishes the SUMOylation pathway. Here, we report that 
selective deletion of Ubc9 within the Treg lineage results in fatal early-onset 
autoimmunity similar to Foxp3 mutant mice. Ubc9-deficient Treg cells exhibit 
severe defects in TCR-driven homeostatic proliferation, accompanied by impaired 
activation and compromised suppressor function. Importantly, TCR ligation 
enhanced SUMOylation of IRF4, a critical regulator of Treg cell function 
downstream of TCR signals, which regulates its stability in Treg cells. Our data 
thus have demonstrated an essential role of SUMOylation in the expansion and 
function of Treg cells.