IL-27-Driven Network Uncovers Regulators of Immune Response in T Helper Cells

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Summary

Interleukin-27 (IL-27) is an immunoregulatory cytokine that suppresses inflammation via multiple mechanisms, including the induction of IL-10; however, the transcriptional network underlying its diverse functions is unknown. They predict 79 transcription factors (TFs) induced by IL-27 in T cells by combining temporal RNA profiling with computational algorithms. They validate 11 known and identify 5 positive- (Cebpb, Fosl2, Tbx21, Hlx, and Atf3) and 2 negative- (Irf9 and Irf8) IL10 regulators, generating an experimentally refined regulatory network for IL10. Two central regulators, Prdm1 and Maf, cooperate to drive the expression of signature genes induced by IL-27 in type 1 regulatory T cells, to mediate IL-10 expression in all T helper cells, and to determine the regulatory phenotype of colonic Foxp3+ regulatory T cells. Prdm1/Maf double-knockout mice develop spontaneous colitis, mimicking lL10-deficient mice. This research elucidates IL-27-driven transcriptional networks and identifies two shared Il10 regulators that orchestrate immunoregulatory programs among T helper cell subsets.

Fig.1 Graphical abstract. (Zhang, 2020)

Research Criteria

Using computational algorithms and high-resolution temporal transcriptional profiling, they predicted the TF network induced by IL-27 during Tr1 differentiation. Prdm1 and Maf were identified as two central nodes of the IL10 regulatory circuits that promoted IL-10 production not only in Tr1 cells, but also in Th1, Th2, Th17, and Treg cells. Genetic deletion of Prdm1 and Maf in T cells (Prdm1/Maf DKO), but not alone, caused spontaneous colitis in mice with features of human inflammatory bowel disease (IBD), highlighting the significance of Prdm1 and Maf crosstalk in regulating immune homeostasis in vivo. Single-cell RNA sequencing (scRNA-seq) of colonic CD4+ T cells in DKO mice uncovered a cluster of Treg cells that lost IL10 expression and acquired proinflammatory signatures.

Sample Type

Cells from mouse colon.

Result—Genetic Deficiency of Prdm1 and Maf, but Not Either Alone in T Cells, Leads to Human IBD-like Spontaneous Colitis Driven by A Unique Cluster of Treg Cells

To characterize the transcriptional changes in T cells that result in spontaneous colitis in DKO mice, scRNA-seq was performed on CD4 T cells from the colonic lamina propria at 3 weeks of age prior to the onset of disease. They gathered a total of 13,535 high-quality single cell profiles that were divided into eight distinct clusters, with two biological replicates for each genotype. The identity of clusters was determined by bulk RNA-seq-derived gene signatures and validated by the expression of key marker genes. The even distribution of the four genotypes within the nave T cell clusters (clusters 1-3) suggests negligible batch effects between samples and comparable phenotypes of nave T cells in the absence of Prdm1 or Maf. Each of the Treg cell clusters (clusters 5-8) was dominated by a different genotype.

Fig.2 Cell cluster UMAP plot and distribution of cells with different genotypes in clusters. (Zhang, 2020)

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Reference

1. Zhang. H.; et al. An il-27-driven transcriptional network identifies regulators of il-10 expression across t helper cell subsets. Cell Reports. 2020,33(8): 108433.