The NFκB-inducing kinase is essential for the developmental programming of skin-resident and IL-17-producing γδ T cells.

Florian Mair,Burkhard Becher,Matthias Hahn,Burkhard Ludewig,Romy Hoeppli,Stefanie Joller,Ari Waisman,Lucas Onder

doi:10.7554/elife.10087

Florian Mair, Burkhard Becher + Show 6 more

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https://doi.org/10.7554/elife.10087

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Abstract

γδ T cells contribute to first line immune defense, particularly through their ability for rapid production of proinflammatory cytokines. The cytokine profile of γδ T cells is hard-wired already during thymic development. Yet, the molecular pathways underlying this phenomenon are incompletely understood. Here we show that signaling via the NFκB-inducing kinase (NIK) is essential for the formation of a fully functional γδ T cell compartment. In the absence of NIK, development of Vγ5(+) dendritic epidermal T cells (DETCs) was halted in the embryonic thymus, and impaired NIK function caused a selective loss of IL-17 expression by γδ T cells. Using a novel conditional mutant of NIK, we could show in vivo that NIK signaling in thymic epithelial cells is essential for the thymic hardwiring of γδ T cell cytokine production.

Highlights

Introduction gdT cells, together with ab T cells and B cells, are the only cells in mammals capable of generating diverse antigenic receptors by somatic gene rearrangement, which enables them to recognize and respond to a vast array of antigens
In the absence of NFB-inducing kinase (NIK) the development of dendritic epidermal T cells (DETCs) is halted in the embryonic thymus Previous studies have shown that the development of DETCs is partially dependent on signaling via the RANK-RANKL axis (Roberts et al, 2012)
Since DETCs are among the very first T cells to develop in ontogeny and populate the epidermis already prior to birth, we analyzed the epidermis of mouse embryos at day 19 post conception

Summary

Introduction

Introduction gdT cells, together with ab T cells and B cells, are the only cells in mammals capable of generating diverse antigenic receptors by somatic gene rearrangement, which enables them to recognize and respond to a vast array of antigens. The second main characteristic of gd T cells is their ability for rapid production of pro-inflammatory cytokines such as INF-g and IL-17 independent of TCR engagement (Sutton et al, 2009). This feature has been suggested to be hardwired in developing gd T cells already during thymic development, probably in dependency of self-antigen recognition (Jensen et al, 2008). The surface molecule CD27, which belongs to the tumor necrosis (TNF) receptor superfamily has been shown to distinguish IFN-g-producing from IL-17-producing gd T cells (Ribot et al, 2009), as does the differential expression of the transcription factors T-bet and RORgt and certain chemokine receptors such as CCR6 (Haas et al, 2009)

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