A role for NF-kB-inducing kinase in regulatory T cell development, tissue maintenance and function
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Abstract
While NIK has been reported to be dispensable for the activation of naïve CD4+ T cells, it was shown to play a crucial part in the maintenance and function of Teff cells. However, its role in thymic development of Treg cells and in the maintenance of Treg cells in lymphoid organs remains controversial. Moreover, the requirement of NIK for Treg cells resident in peripheral tissues such as the colon or the liver as well as in vivo suppression have not been addressed yet. By conditionally deleting NIK in αβ T cells (NIKΔT) in C57BL/6 mice, we detected the requirement for NIK in thymic CD25 TregP and Foxp3lo TregP along with a reduction in mature Foxp3+ Treg cells in the thymus, secondary lymphoid organs and peripheral tissues. Yet, flow cytometric analysis revealed normal numbers of Foxp3+ Treg cells in the thymus and secondary lymphoid organs but a reduction of Foxp3+ Treg cells peripheral tissues such as the colon and the liver in mice with conditional deletion of NIK in Foxp3-expressing cells (NIKΔTreg). In particular, a reduction of the thymus-derived Helios+ Treg cell population was detected in the colon of these mice. Nevertheless, histological analysis of colonic and hepatic tissue sections from NIKΔTreg mice did not show any signs of inflammation. In vitro stimulation with IL-2 did not reveal a defect in proliferation of NIK-deficient Treg cells. Besides, Ki67 staining showed normal proliferation of both ex vivo-isolated NIK-deficient and NIK overexpressing Treg cells. Although in vitro NIK stabilisation in WT Treg cells resulted in normal mRNA levels of apoptosis-related genes Mcl-1, Bak and Bax, co-transfer of WT and NIK-deficient Treg cells into the same lymphopenic host revealed a striking defect in the maintenance of NIK-deficient Treg cells. In particular, the maintenance of TNFR2+ Treg cell population was observed to depend on NIK signalling. Indeed, in vitro stimulation of splenocytes with TNF expanded WT but not NIK-deficient Treg cells. Importantly, while NIK-deficient Treg cells were able to suppress Tconv cells in vitro, they failed to prevent T cell-mediated colitis in Rag1-/- mice in vivo. In summary, being a critical factor for TregP maintenance, our data suggest a novel role for NIK in thymic Treg cell development. While NIK is dispensable for the maintenance of Treg cells in lymphoid organs, it is crucial, however, for the maintenance of certain effector Treg cell subsets residing in peripheral tissues and lymphopenic hosts. Although there is no requirement for NIK in Treg cell-mediated tissue homeostasis of the colon and the liver in steady state, it is essential for Treg cells to suppress T cell-mediated colitis in vivo.