Tumor necrosis factor receptor family costimulation increases regulatory T-cell activation and function via NF-κB

Several drugs targeting members of the TNF superfamily or TNF receptor superfamily (TNFRSF) are widely used in medicine or are currently being tested in therapeutic trials. However, their mechanism of action remains poorly understood. Here, we explored the effects of TNFRSF co-stimulation on murine Foxp3⁺ regulatory T cell (Treg) biology, as they are pivotal modulators of immune responses. We show that engagement of TNFR2, 4-1BB, GITR, and DR3, but not OX40, increases Treg proliferation and survival. Triggering these TNFRSF in Tregs induces similar changes in gene expression patterns, suggesting that they engage common signal transduction pathways. Among them, we identified a major role of canonical NF-κB. Importantly, TNFRSF co-stimulation improves the ability of Tregs to suppress colitis. Our data demonstrate that stimulation of discrete TNFRSF members enhances Treg activation and function through a shared mechanism. Consequently, therapeutic effects of drugs targeting TNFRSF or their ligands may be mediated by their effect on Tregs.     

Hormonal and sensory inputs regulate distinct neuroblast cell cycle properties in adult cricket brain

From invertebrates to humans, it has been demonstrated that new neurons are added to specific brain structures throughout adult life. In the house cricket, adult neurogenesis occurs in the mushroom bodies, the main sensory integrative center of the brain, often considered an analogue of vertebrate hippocampus. We have previously shown that this neurogenesis can be modulated by hormones through the polyamine pathway and by environmental conditions through sensory inputs and the nitric oxide pathway. Environment-induced neurogenesis is independent of juvenile hormone levels, so we addressed the roles of sensory inputs and hormones in the control of neuroblast proliferation. Here, by using double labelling of cells specifically in S phase (5-bromo-2'-deoxyuridine) together with labelling of mitotically active cells in any phase (proliferating cell nuclear antigen), we show that juvenile hormone acts on progenitor cell proliferation by inducing quiescent neuroblasts to enter the cell cycle, whereas sensory inputs act by shortening the cell cycle. Thus, in the adult house cricket, regulation of neuroblast proliferation by hormonal and environmental cues occurs through two independent modes of action.     

MYB is essential for mammary tumorigenesis

MYB oncogene upregulation is associated with estrogen receptor (ER)-positive breast cancer, but disease requirements for MYB function in vivo have not been explored. In this study, we provide evidence of a critical requirement for MYB functions in models of human and murine breast cancer. In human breast cancer, we found that MYB expression was critical for tumor cell growth both in vitro and in vivo in xenograft settings. In transgenic knockout mice, tissue-specific deletion of the murine MYB gene caused a transient defect in mammary gland development that was reflected in delayed ductal branching and defective apical bud formation. In mouse mammary tumor virus (MMTV)-NEU mice where tumors are initiated by activation of HER2, MYB deletion was sufficient to abolish tumor formation. In the more aggressive MMTV-PyMT model system, MYB deletion delayed tumorigenesis significantly. Together, the findings in these transgenic knockout models implied that MYB was critical during an early window in mammary development when it was essential for tumor initiation, even though MYB loss did not exert a lasting impact upon normal mammary function. Two important MYB-target genes that promote cell survival, BCL2 and GRP78/BIP, were each elevated compared with nontransformed mammary epithelial cells, thereby promoting survival as confirmed in colony formation assays in vitro. Taken together, our findings establish a role for MYB at the hub of ER- and HER2-dependent pathways in mammary carcinogenesis.     

c-Myb is required for neural progenitor cell proliferation and maintenance of the neural stem cell niche in adult brain

Ongoing production of neurons in adult brain is restricted to specialized neurogenic niches. Deregulated expression of genes controlling homeostasis of neural progenitor cell division and/or their microenvironment underpins a spectrum of brain pathologies. Using conditional gene deletion, we show that the proto-oncogene c-myb regulates neural progenitor cell proliferation and maintains ependymal cell integrity in mice. These two cellular compartments constitute the neurogenic niche in the adult brain. Brains devoid of c-Myb showed enlarged ventricular spaces, ependymal cell abnormalities, and reduced neurogenesis. Neural progenitor cells lacking c-Myb showed a reduced intrinsic proliferative capacity and reduction of Sox-2 and Pax-6 expression. These data point to an important role for c-Myb in the neurogenic niche of the adult brain.