Tbet Expression in Regulatory T Cells Is Required to Initiate Th1-Mediated Colitis

Abstract

In normal conditions gut homeostasis is maintained by the suppressive activity of regulatory T cells (Tregs), characterized by the expression of the transcription factor FoxP3. In human inflammatory bowel disease, which is believed to be the consequence of the loss of tolerance toward antigens normally contained in the gut lumen, Tregs have been found to be increased and functionally active, thus pointing against their possible role in the pathogenesis of this immune-mediated disease. Though, in inflammatory conditions, Tregs have been shown to upregulate the T helper (Th) type 1-related transcription factor Tbet and to express the pro-inflammatory cytokine IFNγ, thus suggesting that at a certain point of the inflammatory process, Tregs might contribute to inflammation rather than suppress it. Starting from the observation that Tregs isolated from the lamina propria of active but not inactive IBD patients or uninflamed controls express Tbet and IFNγ, we investigated the functional role of Th1-like Tregs in the dextran sulfate model of colitis. As observed in human IBD, Th1-like Tregs were upregulated in the inflamed lamina propria of treated mice and the expression of Tbet and IFNγ in Tregs preceded the accumulation of conventional Th1 cells. By using a Treg-specific Tbet conditional knockout, we demonstrated that Tbet expression in Tregs is required for the development of colitis. Indeed, Tbet knockout mice developed milder colitis and showed an impaired Th1 immune response. In these mice not only the Tbet deficient Tregs but also the Tbet proficient conventional T cells showed reduced IFNγ expression. However, Tbet deficiency did not affect the Tregs suppressive capacity in vitro and in vivo in the adoptive transfer model of colitis. In conclusion here we show that Tbet expression by Tregs sustains the early phase of the Th1-mediated inflammatory response in the gut.

Heterogeneity of T Cells in Atherosclerosis Defined by Single-Cell RNA-Sequencing and Cytometry by Time of Flight

“… 3 , 10 , 29 , 93 – 95 Expression of >1 TF may argue for an enhanced plasticity of cells that are in transition into another T H -type. On the other hand, in the intestine, RORγt + T regs 96 and T H 1-like T regs 97 represent unique lineages that control mucosal immunity. Depending on the condition, these mixed phenotypes result in pro- and/or anti-inflammatory properties.…”

Autocrine TGF-β1 Maintains the Stability of Foxp3+ Regulatory T Cells via IL-12Rβ2 Downregulation

“…These Th1-like Treg cells are generated through the activation of the PI(3)K-Akt-FoxO pathway, which seems to be mediated by IFN-γ, IL-12 or IL-27 stimulation [ 50 ]. Th1-like Treg cells are also observed in various disease settings in mice and humans; however, their role in the pathogenesis of the diseases remains obscure [ 32 , 50 , 51 , 52 , 53 , 54 ]. In addition, whether the Th1-like Treg cells are an intermediate cell population during the development of exTreg Th1 cells from Treg cells under type 1 inflammatory conditions or whether the two are developmentally independent is still unclear.…”

Post-Translational Regulations of Foxp3 in Treg Cells and Their Therapeutic Applications

“…Some factors are known to restrict Treg functions, including chronic exposure to inflammatory cytokines and deprivation of stabilizing factors. Chronic exposure of Tregs to proinflammatory cytokines like IL-1b, IL-6, TNFa, which can antagonize Foxp3 expression and skews the gene expression profile to that of Th17 or Th1 (223)(224)(225). Reduced levels of IL-2 and TGFb (116, 226), on the other hand, can adversely affect the survival of Treg cells.…”