Zfp362 potentiates murine colonic inflammation by constraining Treg cell function rather than promoting Th17 cell differentiation

Abstract

Mucosal barrier integrity and pathogen clearance is a complex process influenced by both Th17 and Treg cells. Previously, we had described the DNA methylation profile of Th17 cells and identified Zinc finger protein (Zfp)362 to be uniquely demethylated. Here, we generated Zfp362−/− mice to unravel the role of Zfp362 for Th17 cell biology. Zfp362−/− mice appeared clinically normal, showed no phenotypic alterations in the T‐cell compartment, and upon colonization with segmented filamentous bacteria, no effect of Zfp362 deficiency on Th17 cell differentiation was observed. By contrast, Zfp362 deletion resulted in increased frequencies of colonic Foxp3+ Treg cells and IL‐10+ and RORγt+ Treg cell subsets in mesenteric lymph nodes. Adoptive transfer of naïve CD4+ T cells from Zfp362−/− mice into Rag2−/− mice resulted in a significantly lower weight loss when compared with controls receiving cells from Zfp362+/+ littermates. However, this attenuated weight loss did not correlate with alterations of Th17 cells but instead was associated with an increase of effector Treg cells in mesenteric lymph nodes. Together, these results suggest that Zfp362 plays an important role in promoting colonic inflammation; however, this function is derived from constraining the effector function of Treg cells rather than directly promoting Th17 cell differentiation.

Identification of master regulator genes controlling pathogenic CD4+ T cell fate in inflammatory bowel disease through transcriptional network analysis

“…An interesting example of this is a recent study using a colitis model induced by transferring naïve CD4 + T cells into Rag2 -/- mice. These authors found that the transfer of naïve T cells deficient in the Zinc finger protein (Zfp)362 displayed a less severe colitis, which was associated with a reduction of Treg function rather than a higher promotion of Th17 differentiation 43 .…”

The dynamic shifts of IL-10-producing Th17 and IL-17-producing Treg in health and disease: a crosstalk between ancient "Yin-Yang" theory and modern immunology

“…While ZFP362 expression is increased in Th17 and can interact with RORγT to promote Th17 differentiation [ 172 ], recent investigations have unveiled its regulatory role in IL-17-producing Treg differentiation. Notably, the level of IL-17-producing Tregs in the mesenteric lymph nodes of Zfp362 −/− mice surpasses that in wild-type mice [ 173 ]. Nevertheless, further exploration is warranted to fully elucidate the mechanisms by which ZFP362 regulates IL-17-producing Treg differentiation.…”