Resolving the field: a role for Nod2 in T cells

NOD2 is primarily recognized as a cytosolic bacterial sensor of peptidoglycan, activating a downstream Rip2/NF-κB-mediated antimicrobial signaling pathway and playing a vital role in host defense against bacterial infections. NOD2 also appears to play a critical role in immune homeostasis, as NOD2 variants have been linked to multiple human inflammatory diseases, including common polymorphisms that increase the risk of Crohn's disease and rare mutations that cause Blau syndrome. The cellular mechanisms through which mutated NOD2 contributes to disease remain unclear and are currently under investigation. A T cell-intrinsic role for Nod2 in infection and inflammation was suggested almost 15 years ago, leading to intense scrutiny in this research area. This review highlights recent studies establishing a T cell-intrinsic role for NOD2 downstream of T-cell receptor and co-receptor signaling and delineates how NOD2 shapes T-cell responses in both homeostasis and disease, with implications for Blau syndrome and Crohn's disease.