Constitutive expression of NF-\u03baB inducing kinase in regulatory T cells impairs suppressive function and promotes instability and pro-inflammatory cytokine production

Fanny Polesso,Arian Anderson,Susan E Murray,Minhazur Sarker,David C Parker

doi:10.1038/s41598-017-14965-x

Fanny Polesso, Arian Anderson + Show 3 more

Open Access

https://doi.org/10.1038/s41598-017-14965-x

Copy DOI

Abstract

CD4+Foxp3+ regulatory T cells (Tregs) are indispensable negative regulators of immune responses. To understand Treg biology in health and disease, it is critical to elucidate factors that affect Treg homeostasis and suppressive function. Tregs express several costimulatory TNF receptor family members that activate non-canonical NF-κB via accumulation of NF-κB inducing kinase (NIK). We previously showed that constitutive NIK expression in all T cells causes fatal multi-organ autoimmunity associated with hyperactive conventional T cell responses and poor Treg-mediated suppression. Here, we show that constitutive NIK expression that is restricted to Tregs via a Cre-inducible transgene causes an autoimmune syndrome. We found that constitutive NIK expression decreased expression of numerous Treg signature genes and microRNAs involved in Treg homeostasis and suppressive phenotype. NIK transgenic Tregs competed poorly with WT Tregs in vivo and produced pro-inflammatory cytokines upon stimulation. Lineage tracing experiments revealed accumulation of ex-Foxp3+ T cells in mice expressing NIK constitutively in Tregs, and these former Tregs produced copious IFNγ and IL-2. Our data indicate that under inflammatory conditions in which NIK is activated, Tregs may lose suppressive function and may actively contribute to inflammation.

Highlights

NF-κB inducing kinase (NIK) (MAP3K14) is an essential kinase that links several co-stimulatory TNF receptor family members (TNFRs) to non-canonical NF-κB activation
We previously showed that T cell restricted constitutive NIK expression in CD4Cre/NIK transgenic (NIKtg) mice activates non-canonical NF-κB in T cells and causes early onset lethal multi-organ autoimmunity[36]
Consistent with our prior report, we found that NIK expression intrinsically impaired the ability of in vitro generated that differ between CD4+Foxp3GFP+ (Treg) (iTregs) to suppress Tconv cell proliferation (Fig. 1a,b and Supplementary Fig. S1)

Summary

Introduction

NIK (MAP3K14) is an essential kinase that links several co-stimulatory TNF receptor family members (TNFRs) to non-canonical NF-κB activation. These receptors include TNFR2, TNFRSF4 (CD134, OX40), TNFRSF18 (GITR), and TNFRSF9 (CD137, 4-1BB), which all have been implicated in decreasing Treg function or phenotypic stability[21,22,23,24,25,26,27,28,29]. Aberrations in the non-canonical NF-κB pathway downstream of NIK can lead to autoimmunity in mice[36,38,39,40,41,42] Despite this growing evidence that aberrant signaling downstream of NIK in effector T cells can contribute to autoimmune pathogenesis, the effect of NIK on Treg function is unknown. NIK overexpression altered Treg signature gene expression, impaired Treg phenotypic stability, and de-repressed pro-inflammatory cytokine production by Tregs

Methods

Results

Conclusion