RORγt expression in Tregs promotes systemic lupus erythematosus via IL-17 secretion, alteration of Treg phenotype and suppression of Th2 responses

Abstract

Systemic lupus erythematosus (SLE) is a common autoimmune disorder with a complex and poorly understood immunopathogenesis. However, a pathogenic role for the T helper type 17 (Th17) axis was demonstrated by many studies, while regulatory T cells (T ) were shown to mediate protection. Recently, we and others characterized a novel and independent T cell population expressing both the T characteristic transcription factor forkhead box protein 3 (FoxP3) and the Th17-defining retinoic acid receptor-related orphan nuclear receptor γt (RORγt). Studies in a model of acute glomerulonephritis unveiled potent regulatory, but also proinflammatory, functions of RORγt FoxP3 T . This bi-functional nature prompted us to suggest the name 'biT '. Importantly, the pathogenic biT effects were dependent upon expression of RORγt. We thus aimed to evaluate the contribution of RORγt FoxP3 biT to pristane-induced SLE and explored the therapeutic potential of interference with RORγt activation. Our analyses revealed expansion of IL-17 producing biT in a distinctive time-course and organ-specific pattern, coincident with the development of autoimmunity and tissue injury. Importantly, specific ablation of RORγt activation in endogenous biT resulted in significant amelioration of pristane-induced pulmonary vasculitis and lupus nephritis. As potential mechanisms underlying the observed protection, we found that secretion of IL-17 by biT was abrogated completely in FoxP3 × RORC mice. Furthermore, T showed a more activated phenotype after cell-specific inactivation of RORγt signalling. Finally, and remarkably, biT were found to potently suppress anti-inflammatory Th2 immunity in a RORγt-dependent manner. Our study thus identifies biT as novel players in SLE and advocates RORγt-directed interventions as promising therapeutic strategies.

Developmental endothelial locus‐1 (Del‐1) antagonizes Interleukin‐17‐mediated allergic asthma

“…The orphan retinoid receptor, RORc, which is the master transcription factor in IL-17-secreting cells, appears to be required for IL-17 production. 24,25 Transduction of naive T cells with RORc induces the development of IL-17-secreting cells. 26,27 In addition, activation of STAT3 is necessary to induce RORc and induce expression of IL-17 by increasing the expression of RORc.…”

The role and mechanism of vitamin D‐mediated regulation of Treg/Th17 balance in recurrent pregnancy loss

“…15,22 In the pathological environment, Foxp3 + IL-17 + T cells mainly play a pro-inflammatory role. [22][23][24] In research studies, intravenous immunoglobulin G treatment and lymphocyte immunotherapy have commonly been applied to modulate the Treg/Th17 imbalance in pregnant women with RPL. [25][26][27] In a study using an abortion-prone mouse model, transfer of pregnancyinduced CD4 + CD25 + Treg cells was able to reverse the elevated abortion rate which was induced by IL-17.…”

Regulatory T cells in renal disease

“…Depletion studies in pristane‐induced models of lupus nephritis have demonstrated that endogenous Stat3‐expressing Foxp3 + Tregs (‘Treg17’) afford protection from injury, as Foxp3‐Cre deletion of Stat3 led to heightened Th17 responses and less Treg17 cell recruitment to the kidney, likely due to impaired CCR6 expression . The same group showed that in the same model, Foxp3 + RORγt + Tregs (‘biTregs’) were pathogenic, at least in part, because RORγt induce the secretion of IL‐17 in biTreg cells …”

“…37 The same group showed that in the same model, Foxp3 + RORct + Tregs ('biTregs') were pathogenic, at least in part, because RORct induce the secretion of IL-17 in biTreg cells. 38 A number of treatments in several murine models of lupus have been associated with increased Treg number or function, including, in MRL/lpr strain, IL-33 inhibition, piperlongumine and the 4hydroxyquinoline-3-formamide derivative (known as Y27) [39][40][41] ; in NZBxW/F1 mice, IL-2/IL-2 mAb immune complexes, G-CSF and tuftsin-phosphorylcholine [42][43][44] ; and in the bm12?B6 chronic graftversus-host model of lupus nephritis, microRNA-21 deficiency. 45 Progesterone may also be important for optimal Treg number and function, as progesterone-deficient Nba2 mice have increased antichromatin IgG and proteinuria associated with a decrease in Tregs.…”