The expression of co-inhibitory receptors, such as CTLA-4 and PD-1, on effector T cells is a key mechanism for ensuring immune homeostasis. Dysregulated expression of co-inhibitory receptors on CD4
T ...cells promotes autoimmunity, whereas sustained overexpression on CD8
T cells promotes T cell dysfunction or exhaustion, leading to impaired ability to clear chronic viral infections and diseases such as cancer
. Here, using RNA and protein expression profiling at single-cell resolution in mouse cells, we identify a module of co-inhibitory receptors that includes not only several known co-inhibitory receptors (PD-1, TIM-3, LAG-3 and TIGIT) but also many new surface receptors. We functionally validated two new co-inhibitory receptors, activated protein C receptor (PROCR) and podoplanin (PDPN). The module of co-inhibitory receptors is co-expressed in both CD4
and CD8
T cells and is part of a larger co-inhibitory gene program that is shared by non-responsive T cells in several physiological contexts and is driven by the immunoregulatory cytokine IL-27. Computational analysis identified the transcription factors PRDM1 and c-MAF as cooperative regulators of the co-inhibitory module, and this was validated experimentally. This molecular circuit underlies the co-expression of co-inhibitory receptors in T cells and identifies regulators of T cell function with the potential to control autoimmunity and tumour immunity.
Interleukin-27 (IL-27) is an immunoregulatory cytokine that suppresses inflammation through multiple mechanisms, including induction of IL-10, but the transcriptional network mediating its diverse ...functions remains unclear. Combining temporal RNA profiling with computational algorithms, we predict 79 transcription factors induced by IL-27 in T cells. We validate 11 known and discover 5 positive (Cebpb, Fosl2, Tbx21, Hlx, and Atf3) and 2 negative (Irf9 and Irf8) Il10 regulators, generating an experimentally refined regulatory network for Il10. We report two central regulators, Prdm1 and Maf, that cooperatively drive the expression of signature genes induced by IL-27 in type 1 regulatory T cells, mediate IL-10 expression in all T helper cells, and determine the regulatory phenotype of colonic Foxp3+ regulatory T cells. Prdm1/Maf double-knockout mice develop spontaneous colitis, phenocopying ll10-deficient mice. Our work provides insights into IL-27-driven transcriptional networks and identifies two shared Il10 regulators that orchestrate immunoregulatory programs across T helper cell subsets.
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•IL-27-driven transcriptional network in CD4 T cells unravels key Il10 regulators•Systematic characterization of the function of 16 Il10 regulators by RNA-seq•Identification of transcription factors associated with Il10 in multiple T cell subsets•Prdm1 and Maf are critical for Il10 production and intestinal immune homeostasis
Zhang et al. construct a transcriptional network for IL-27-mediated Il10 production in CD4 T cells, characterize the function of 16 Il10 regulators, and uncover the role of two transcription factors, Prdm1 and Maf, in driving Il10 production in all T helper cells and in maintaining immune homeostasis in the colon.
Prostate cancer is the second leading cause of cancer-related death in men in the US. The rat is a larger rodent, and thus more amenable to study by instrumentation and drug candidate testing ...(Mordenti, 1986). Depending on the specific drug candidates being tested, different model organisms have distinct advantages with respect to the similarity of their cytochrome P450 (CYP) activity to human. We have focused on the oncogene MYC and the tumor suppressor P53 to develop a rat model that would recapitulate the natural history of human prostate cancer. MYC is commonly overexpressed in prostate cancer and is associated with disease initiation and progression. Loss of p53 is frequently detected in metastatic and castration resistant prostate cancer, but it is desirable to understand the consequences of P53 loss in the early stages of prostate cancer. Thus, we have created and characterized a rat model of prostate cancer by combining Hoxb13 -driven overexpression of MYC and deletion of TP53 gene. We have observed both preneoplastic lesions and overt prostate adenocarcinoma in these rats (Hoxb13-MYC+|P53–/– ). At 20 weeks, four of eight rats developed highly aggressive tumors that metastasized to pelvic lymph nodes. The tumors consistently expressed MYC and the cell proliferation marker Ki67, and showed decreased expression of phosphatase and tensin homolog (PTEN), Hoxb13, and androgen receptor (AR) by immunohistochemistry. These expression patterns remained unchanged during metastasis. These data demonstrate that it is feasible to develop a rat model that recapitulates important features of human prostate cancer including the metastatic phenotype.
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