Nedd4 family interacting protein 1 limits effector CD4 T cell abundance, cytokine production and inflammation. (HUM3P.248)

Abstract

Abstract When effector T cells fail to appropriately terminate signaling responses, autoimmune diseases such as multiple sclerosis and inflammatory bowel disease may occur. Signaling in a cell may be terminated by the ubiquitylation and degradation of key signaling transducers. The ubiquitylation cascade is a well studied sequence of orchestrated reactions by which ubiquitin is added on to a substrate protein to, among other things, target that protein for degradation. Ndfip1, or Nedd4 family interacting protein 1, activates the function of E3 ligases, which play important roles in the ubiquitylation cascade. Ndfip1 works with Itch and Nedd4-2 E3 ligases to degrade the IL-4 transcription factor, JunB. Thus in mice that lack Ndfip1, there is unrestricted IL-4 secretion, which leads to an inflammatory phenotype. However, this fails to explain why human SNPs in Ndfip1 have been linked to two autoimmune conditions where TH1 and/or TH17 effector function is unrestrained, namely, multiple sclerosis and inflammatory bowel disease. Mice lacking Ndfip1 show increased overall frequencies of activated T cells and of IFNγ+ and IL-17A+ CD4 T cells, which suggests a general defect in limiting effector T cell abundance. We present data indicating that Ndfip1 limits inflammation in two models of inflammatory bowel disease. Understanding how Ndfip1 limits effector T cell function could clarify how human diseases such as inflammatory bowel disease and multiple sclerosis develop.