Maintenance of immune homeostasis involves a synergistic relationship between the host and the microbiome. Canonical interferon (IFN) signaling controls responses to acute microbial infection, through engagement of the STAT1 transcription factor. However, the contribution of tonic levels of IFN to immune homeostasis in absence of acute infection remains largely unexplored. We report that STAT1 KO mice spontaneously developed an inflammatory disease marked by myeloid hyperplasia and splenic accumulation of hematopoietic stem cells. Moreover, these animals developed inflammatory bowel disease. Profiling gut bacteria revealed a profound dysbiosis in absence of tonic IFN signaling, which triggered expansion of TH17 cells and loss of splenic Treg cells. Reduction of bacterial load by antibiotic treatment averted the TH17 bias, and blocking IL17 signaling prevented myeloid expansion and splenic stem cell accumulation. Thus, tonic IFNs regulate gut microbial ecology, which is crucial for maintaining physiologic immune homeostasis and preventing inflammation.
Maintenance of immune homeostasis involves a synergistic relationship between the host and the microbiome. Canonical interferon (IFN) signaling controls responses to acute microbial infection, through engagement of the STAT1 transcription factor. However, the contribution of tonic levels of IFN to immune homeostasis in absence of acute infection remains largely unexplored. We report that STAT1 KO mice spontaneously developed an inflammatory disease marked by myeloid hyperplasia and splenic accumulation of hematopoietic stem cells. Moreover, these animals developed inflammatory bowel disease. Profiling gut bacteria revealed a profound dysbiosis in absence of tonic IFN signaling, which triggered expansion of TH17 cells and loss of splenic Treg cells. Resolution of dysbiosis by antibiotic treatment averted the TH17 bias, and blocking IL17 signaling prevented myeloid expansion and splenic stem cell accumulation. Thus, tonic IFNs regulate gut microbial ecology, which is crucial for maintaining physiologic immune homeostasis and preventing inflammation.
Immune health requires innate and adaptive immune cells to engage precisely balanced pro- and anti-inflammatory forces. We employ the concept of chemical immunophenotypes to classify small molecules functionally or mechanistically according to their patterns of effects on primary innate and adaptive immune cells. The high-specificity, low-toxicity cyclin dependent kinase 8 (CDK8) inhibitor DCA exerts a distinct tolerogenic profile in both innate and adaptive immune cells. DCA promotes T
reg
and Th2 differentiation, while inhibiting Th1 and Th17 differentiation, in both murine and human cells. This unique chemical immunophenotype led to mechanistic studies showing that DCA promotes T
reg
differentiation in part by regulating a previously undescribed CDK8-GATA3-FOXP3 pathway that regulates early pathways of Foxp3 expression. These results highlight previously unappreciated links between T
reg
and Th2 differentiation and extend our understanding of the transcription factors that regulate T
reg
differentiation and their temporal sequencing. These findings have significant implications for future mechanistic and translational studies of CDK8 and CDK8 inhibitors.
Immune health requires innate and adaptive immune cells to engage precisely balanced pro-and anti-inflammatory forces. A holistic understanding of how individual small molecules affect this balance is essential to anticipate immune-related side effects, select mitigating immunomodulatory therapies and highlight novel utility as immunomodulators. We previously showed that the high-specificity, low-toxicity cyclin dependent kinase 8 (CDK8) inhibitor DCA promotes tolerogenic effects in innate immune cells. Here, we demonstrate that DCA exerts a novel profile of tolerogenic activity on CD4 + T cells, promoting Treg and Th2 while inhibiting Th1 and Th17 differentiation. DCA enhances human Treg differentiation and our models demonstrate clear tolerogenic function of DCA-driven Tregs in the absence of confounding contribution from DCA-innate immune interactions. DCA engages unique mechanisms, including specifically enhancing early Foxp3 expression via regulating c-Jun phosphorylation, to promote Treg differentiation. CDK8 inhibitors are currently being developed to treat cancer; our findings suggest that the potential blunting of host-versus-tumor effects may warrant ancillary pro-inflammatory agents. Importantly, these results highlight novel utility of DCA as an immunomodulator, not only in vivo, but also in ex vivo cellular therapy.
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