Kruppel-like Factor 14 as Driver of Regulatory T-Cell Activity in Intestinal Inflammation

Regulatory T cells (Treg cells) have been previously found to play a major role in controlling chronic intestinal inflammation. In the murine model of colitis induced by adoptive transfer of CD4⁺CD45RB^high T cells, Treg cells produce anti-inflammatory cytokines such as interleukin-10 and transforming growth factor-β and can suppress intestinal inflammation by inhibiting effector T-cell activity and expansion.1, 2 Such effects can be obtained by cotransfer of either naturally occurring Treg cells or inducible Treg cells that have been expanded in vitro.1, 3 It may therefore be surprising that the expansion of functionally active mucosal Treg cells found in patients with inflammatory bowel diseases (IBD) fails to prevent or reverse disease. This is likely explained by the massive expansion of effector T cells in IBD, which leads to a reduction in the ratio between Treg cells and effector T cells, even though the number of both cell types is increased.⁴ This concept has led to initial trials to suppress chronic intestinal inflammation in IBD patients by adoptive transfer of expanded naturally occurring Treg cells.⁵ Collectively, these findings highlight the crucial relevance of Treg cells in intestinal inflammation. However, the molecular signals that drive functional activity of Treg cells in the inflamed mucosa in colitis are poorly understood.

In the present issue of Cellular and Molecular Gastroenterology and Hepatology, Sarmento et al⁶ have analyzed potential regulators of Treg activity in chronic intestinal inflammation. They identified Kruppel-like factor 14 (KLF14) as an important regulator of Treg function. Specifically, KLF14 was found to control the expression of forkhead box P3 (FoxP3), the master transcription factor of Treg cells, via transcriptional mechanisms involving methylation and chromatin remodeling at the Treg-specific demethylation region (TSDR) within the promoter. Inactivation of KLF14 led to hyperactivation of Treg cells and augmented their suppressive capacities.

To analyze the relevance of KLF14 in intestinal inflammation in vivo, they performed additional studies using both dextran sodium sulfate and CD4⁺CD45RB^high adoptive transfer colitis models. In the dextran sodium sulfate colitis model, KLF14 deficiency reduced the severity of the colitis, consistent with the idea that augmented Treg activity protects mice from colitis. Similarly, transfer of KLF14-deficient or wild-type CD4⁺CD25⁺ T reg cells 14 days after adoptive transfer of wild-type CD4⁺CD45RB^high T cells showed that KLF14-deficient Treg cells were far superior in preventing disease progression.

This study has therefore identified KLF14 as new negative regulator of the functional activity of FoxP3-expressing mucosal Treg cells in colitis by directly inhibiting FoxP3 expression. Consistent with this idea, the investigators noted that KLF14 and FoxP3 expression levels in mucosal CD4⁺ T cells are inversely correlated in Crohn’s disease, where KLF14 expression is reduced while FoxP3 expression is increased as compared with control subjects.

These new findings provide insight into the mechanisms controlling Treg activity and suggest novel approaches to modulation of KLF14 expression as a therapeutic approach. For example, suppression of KLF14 expression may represent an effective means of increasing Treg cells activity in IBD patients.⁵ This would require further work, as technologies to efficiently silence KLF14 expression in vivo in human Treg cells are not yet available. Furthermore, the findings in this study may have broader relevance for other autoimmune and chronic inflammatory disorders in which insufficient Treg cell activity has been reported. Future studies should address KLF14 levels in such disorders to clarify whether modulation of KLF14 is specifically relevant for intestinal Treg cells or Treg cells in general in a variety of chronic inflammatory diseases.