NIK-dependent RelB Activation Defines a Unique Signaling Pathway for the Development of Vα14i NKT Cells

Abstract

A defect in RelB, a member of the Rel/nuclear factor (NF)-κB family of transcription factors, affects antigen presenting cells and the formation of lymphoid organs, but its role in T lymphocyte differentiation is not well characterized. Here, we show that RelB deficiency in mice leads to a selective decrease of NKT cells. RelB must be expressed in an irradiation-resistant host cell that can be CD1d negative, indicating that the RelB expressing cell does not contribute directly to the positive selection of CD1d-dependent NKT cells. Like RelB-deficient mice, aly/aly mice with a mutation for the NF-κB–inducing kinase (NIK), have reduced NKT cell numbers. An analysis of NK1.1 and CD44 expression on NKT cells in the thymus of aly/aly mice reveals a late block in development. In vitro, we show that NIK is necessary for RelB activation upon triggering of surface receptors. This link between NIK and RelB was further demonstrated in vivo by analyzing RelB+/− × aly/+ compound heterozygous mice. After stimulation with α-GalCer, an antigen recognized by NKT cells, these compound heterozygotes had reduced responses compared with either RelB+/− or aly/+ mice. These data illustrate the complex interplay between hemopoietic and nonhemopoietic cell types for the development of NKT cells, and they demonstrate the unique requirement of NKT cells for a signaling pathway mediated by NIK activation of RelB in a thymic stromal cell.

NF-κB-Inducing Kinase Establishes Self-Tolerance in a Thymic Stroma-Dependent Manner

“…Based on the findings that production of p52 is impaired in NIK aly/aly thymic stroma (Fig. 1C) and that NIK has been demonstrated necessary for the production of NK T cells through the action of RelB (43,44), we further speculate that the NIK-related signaling pathway(s) activate the NF-B complex in thymic stroma mainly consisting of p52/RelB heterodimers to generate the thymic microenvironment that is necessary for the establishment of self-tolerance. The molecular link between the NF-B activation pathway and the regulatory mechanisms of the thymic microenvironment as well as of autoimmunity requires further study.…”

Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models

“…In the thymus, the generation of early NK1.1 À natural killer T cell (NKT) precursors is dependent on RelB expression in radiation-resistant thymic stromal cells (Elewaut et al, 2003;Sivakumar et al, 2003), whereas T-cell-intrinsic expression of RelB is necessary for the proliferation and survival of single positive thymocytes during the final stages of development (Guerin et al, 2002). In mature CD4 þ T cells, RelB is required for normal Th1 function and IFNg production, with impaired Th1 differentiation of relb À/À T cells linked to a decrease in Stat4 expression (Corn et al, 2005).…”

NKT cell development in the absence of the autoimmune regulator gene (Aire)

“…The convergence of signaling factors influencing Aire expression and NKT development is perhaps best illustrated in mice lacking NF-kB family members such as RelB or NIK [2]. These mice have significantly reduced levels of Aire [20] and NKT cells [21,22], but relatively normal conventional T-cell numbers. A similar correlation between Aire expression and NKT cell numbers was reported in lymphotoxin-deficient mice [23,24], although the link between the expression of lymphotoxin and Aire-dependent genes has been disputed in more recent studies [25][26][27].…”