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

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.

Sirtuin4 suppresses the anti‐neuroinflammatory activity of infiltrating regulatory T cells in the traumatically injured spinal cord

“…38 Meanwhile, SIRT2 deacetylates p65 to inhibit nuclear factor-jB (NF-jB) activity. 39 Because Akt and NF-jB are both important for Treg cell activity, [40][41][42][43] it is likely that up-regulation of SIRT2 influences Treg cell immunosuppressive function. However, because the exact role of Akt and NF-jB in Treg cell activity is still under debate, it is difficult to deduce the effect of SIRT2.…”

Notch and NF-κB: Coach and Players of Regulatory T-Cell Response in Cancer

“…Interestingly, Murray et al genetically manipulated the NIK expression in mice and demonstrated that the NIK deletion in T cells specifically impairs the maintenance of peripheral Foxp3 + Tregs, thus suggesting a Tregs intrinsic function for the noncanonical pathway ( 35 ). Alternatively, the lineage-specific constitutive activation of NIK in Treg cells induces an alteration of their functions and gene signature (Gitr + CD25 + Foxp3 + ), leading to the development of an autoimmune syndrome ( 36 ).…”

“…For a pharmacological approach, pentoxifylline (PTXF) that selectively degrades c-Rel is indicated, as well as inhibitors of Treg-mediated suppression activity by CXCR4 antagonists, such as plerixafor (AMD3100) or peptide R-29. The dotted line refers to hypothetical Notch1- and/or Notch3-induced CXCR4 modulation in Treg cells, whereas the black curved-line indicates the Notch3-enhanced CTLA4 expression in N3-ICtg Tregs ( 36 ). Cancer-associated cells once activated in a tumor microenvironment can express many proinflammatory genes, including stromal cell-derived factor 1 (SDF1), the cognate ligand of CXCR4, partly in an NF-κB-dependent manner ( 23 ).…”

The Impact of Dietary Components on Regulatory T Cells and Disease

“…Signals driven by the cytokine milieu (55-59), co-stimulatory molecules (60)(61)(62) and the strength of the TCR signaling (63)(64)(65) allow Tregs to adapt to the immune environment through e.g., changes in FOXP3 expression. Several studies have shown that, under certain inflammatory conditions, some Tregs secrete pro-inflammatory cytokines and lose their suppressive function (13,(66)(67)(68)(69)(70)(71)(72). Interestingly, phenotypically distinct Treg subsets in humans and mice have been described that mirror CD4 + Th cell populations by specific co-expression of chemokine receptors, cytokines, and lineage specifying-transcription factors classically associated with Th cells (18,(73)(74)(75)(76).…”