The NFκB inducing kinase - regulating the function of dendritic cells and γδ T cells

Abstract

SUMMARY In order to avoid fatal autoimmunity, the immune system needs to maintain a careful balance between reactivity towards invading pathogens, and tolerance towards self-antigens. One of the most prominent regulators involved in these processes is the transcription factor family of NFκB (nuclear factor kappa-light-chain- enhancer of B cells). Two main pathways can activate NFκB: the classical, and the alternative or non-canonical pathway. In case of the latter the NFκB-inducing kinase (NIK) is the most important signal conveyor. Signaling via NIK has been shown to be essential for the development of lymph nodes and the normal function of many immune cell types, including B cells, αβ T cells and dendritic cells (DCs). Therefore, mice deficient for NIK show diverse phenotypes in different cellular compartments, which impedes the clarification of the role of NIK in one specific cell type. Within this thesis, I describe a novel mouse line that allows for conditional deletion of NIK in a time- and tissue-specific manner. Using these NIKflox/flox mice we could show that NIK signaling plays an essential role both in T cells and DCs for the induction of experimental autoimmune encephalomyelitis (EAE), which is the animal model for multiple sclerosis (MS). DC-specific deletion of NIK led to an impaired ability of DCs to produce pro-inflammatory cytokines, and to a selective loss of skin- draining Langerin+ DCs in the lymph node. Hence, loss of NIK signaling seems to have very discrete effects on the migration and function of DCs. Furthermore, we aimed at investigating the development and function of γδ T cells in the absence of functional NIK signaling. γδ T cells are increasingly recognized as important effector cells at the interface of innate and adaptive immunity, particularly due to their ability for immediate secretion of pro-inflammatory cytokines. We found that NIK-deficient lymphoid and tissue-resident γδ T cells were selectively impaired in their ability for IL-17 production, while their expression of IFN-γ remained unchanged. In addition, the pool of dendritic epidermal T cells (DETCs) in the skin of NIK-/- mice was disturbed in that most of the DETCs lost expression of the canonical Vγ5Vδ1 T cell receptor. This was due to a developmental block of Vγ5+ precursor cells in the embryonic thymus, most likely caused by the absence of Skint-1 expression on NIK-deficient thymic epithelial cells. In summary, these results identify a previously unknown role of NIK in the function of γδ T cells. In addition, the novel NIKflox/flox mouse line will be a unique tool for understanding the function of NIK in different immune compartments in more detail.