Abstract
The NF-κB family member RelB is an important transcription factor that is capable of regulating diverse immune and inflammatory responses. However, its role in the regulation of Foxp3+ regulatory T cells (Tregs) in vivo is poorly defined. In this study, we demonstrated that germline deletion of Relb resulted in systemic autoimmunity, which is associated with significant accumulation of Foxp3+ Tregs in lymphoid and nonlymphoid organs. Foxp3+ Tregs from RelB-deficient mice were functional and capable of suppressing T effector cells in vitro and in vivo, but Foxp3- T effector cells from RelB-deficient mice showed features of hyperactivation and spontaneously produced high levels of IL-2. Surprisingly, mice with conditional deletion of Relb in T cells (Cd4CreRelbf/f mice) or specifically in Foxp3+ Tregs (Foxp3CreRelbf/f mice) did not show signs of autoimmunity and had similar frequencies of Foxp3+ Tregs in the periphery as wild-type C57BL/6 controls. Both strains of conditional knockout mice also had a normal conventional T cell compartment. However, reconstituting Rag-1-/-Relb-/- hosts with wild-type C57BL/6 bone marrow cells led to hyperactivation of T effector cells, as well as marked expansion of Foxp3+ T cells. These data suggest that the autoimmune phenotype in germline RelB-deficient mice is most likely caused by T cell-extrinsic mechanisms, and further studies are warranted to uncover such mechanisms.