Protein ublquitlnatlon is an important means of posttranslational modification which plays an essential role in the regulation of vadous aspects of leukocyte development and function.The specificity of ublqultln tagging to s protein subetrate is detsrmlned by E3 ubiquitln ligases via defined E3-substrate interactions.In this review,we will focus on two E3,gases,VHL and Itch,to discuss the latest progress In understanding their roles in the differentiation and function of CD4+ T helper cell subsets,the stability of regulatory T cells,effector function of CD8+ T cells,as well as the development and maturation of Innate lymphoid cells.The biological implications of these E3 ublqultln Ilgases will be highlighted In the context of normal and dysregulated immune responses including the control of homeostasis,inflammation,auto-immune responses and anti-tumor immunity.Further elucidation of the ublqultln system in immune cells will help in the design of new therapeutic interventions for human immunological diseases and cancer.