ABSTRACT A TALE OF TWO LIGASES: ITCH AND CUL5 LIMIT T CELL-MEDIATED INFLAMMATION Natania Field Paula Oliver Rapid, robust proliferation and cytokine production by CD4 T cells are crucial steps in mounting anti-pathogen responses, but these processes must be tightly controlled. Excess proliferation or differentiation into proinflammatory subtypes, including Th2 and Th9 cells, can result in diseases such as asthma. One regulatory mechanism that prevents these outcomes is ubiquitination. By facilitating the binding of ubiquitin chains on specific target substrates, E3 ubiquitin ligases can mark these substrates for degradation and limit their ability to signal. Using mice deficient in Itch and mice with a T cell conditional deletion of Cullin 5 (Cul5), we have identified novel roles for these two E3 ubiquitin ligases in limiting type 2 inflammation. While it is well established that Itch limits Th2 cell differentiation by restricting IL-4 production, we have uncovered a previously unappreciated role for this protein in restricting CD4 T cell proliferation. Itch promotes degradation of WW-domain binding protein 2 (WBP2), thereby limiting T cell cycle entry and in vivo proliferation. Additionally, we demonstrate for the first time that Cul5 plays a crucial role in uninfected T cell function. Mice that lacked Cul5 in CD4 T cells had spontaneous type 2 lung inflammation and increased susceptibility to experimental asthma. Our evidence suggests that Cul5 acts in a complex with Cytokine-inducible SH2 domain-containing protein (CIS) in primary CD4 T cells to limit Th2 and Th9 differentiation. These findings demonstrate that Itch and Cul5 act through distinct mechanisms to restrict type 2 inflammation. While both proteins may be candidates for targeted asthma therapies, their different mechanisms of action lead to different predictions for how such therapies would work, and who would benefit from them.