NF-κB–inducing kinase plays an essential T cell–intrinsic role in graft-versus-host disease and lethal autoimmunity in mice

Abstract

NF-κB-inducing kinase (NIK) is an essential upstream kinase in noncanonical NF-κB signaling. NIK-dependent NF-κB activation downstream of several TNF receptor family members mediates lymphoid organ development and B cell homeostasis. Peripheral T cell populations are normal in the absence of NIK, but the role of NIK during in vivo T cell responses to antigen has been obscured by other developmental defects in NIKdeficient mice. Here, we have identified a T cell-intrinsic requirement for NIK in graft-versus-host disease (GVHD), wherein NIK-deficient mouse T cells transferred into MHC class II mismatched recipients failed to cause GVHD. Although NIK was not necessary for antigen receptor signaling, it was absolutely required for costimulation through the TNF receptor family member OX40 (also known as CD134). When we conditionally overexpressed NIK in T cells, mice suffered rapid and fatal autoimmunity characterized by hyperactive effector T cells and poorly suppressive Foxp3 + Tregs. Together, these data illuminate a critical T cell-intrinsic role for NIK during immune responses and suggest that its tight regulation is critical for avoiding autoimmunity.

NF-κB–Inducing Kinase in Thymic Stroma Establishes Central Tolerance by Orchestrating Cross-Talk with Not Only Thymocytes but Also Dendritic Cells

“…2C), suggesting that NIK mutation in hematopoietic cells also plays a role in Treg production. This finding supports a T cell-intrinsic role of NIK (15)(16)(17)(18)(19)(20). However, one study has suggested that the phenotypes of T cells from aly mice are attributable to abnormal function of DCs lacking normal NIK (21).…”

“…Taken together, these results suggest that impaired Treg production in aly mice is at least partly stroma dependent and associated with the defect in the production of mature CD80 high mTECs. Although the data presented above suggested that impaired de novo production of Tregs in aly mice is thymic stroma dependent, we and others previously demonstrated that NIK mutation also affects T cell reactivity in a cell-autonomous manner (15)(16)(17)(18)(19)(20) that can affect Treg lineage commitment (4). Therefore, we examined whether impaired de novo production of Tregs also depends on NIK in hematopoietic cells by generating reciprocal BM chimeras.…”

“…Although cross-presentation of mTEC-derived self-Ags by thymic DCs has been recognized as an important interplay between mTECs and DCs (14), little is known about how the thymic stroma affects the development and function of thymic DCs. The issue becomes more complex when considering the role of NIK in this context because NIK has been implicated in the intrinsic function of hematopoietic cells including T cells (15)(16)(17)(18)(19)(20) as well as DCs (12,21). In this regard, it is particularly important to note that the cell-autonomous role of NIK in T cells has recently been debated.…”

Opposing Roles for TRAF1 in the Alternative versus Classical NF-κB Pathway in T Cells

“…Thus, we sought to investigate other pathways downstream of 4-1BB that could affect proliferation and cytokine production. Recently it has been reported that NIK, an activator of the alternative NF-B pathway, is absolutely required for costimulation through the TNF receptor family member OX40 in graft-versus-host disease (43). A previous report showed that overexpresson of 4-1BB in 293 cells leads to the appearance of p52 (31).…”

TNF Receptor-Associated Factor (TRAF) Signaling Network in CD4⁺ T-Lymphocytes

“…NIK expressed by CD4 + T cells plays an essential role in graft-versus-host disease, and NIK signaling via OX40 is required for the lethal autoimmunity (Murray et al 2011). NIK is also important for generation and maintenance of CD4 + and CD8 + memory T cells in response to LCMV infection (Rowe et al 2013).…”