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T cell acute lymphoblastic leukemia (T-ALL) is an aggressive immature T cell cancer. Mutations in IL7R have been analyzed genetically, but downstream effector functions such as STAT5A and STAT5B hyperactivation are poorly understood. Here, we studied the most frequent and clinically challenging [STAT5B.sup.N642H] driver in T cell development and immature T cell cancer onset and compared it with STAT5A hyperactive variants in transgenic mice. Enhanced STAT5 activity caused disrupted T cell development and promoted an early T cell progenitor-ALL phenotype, with upregulation of genes involved in T cell receptor (TCR) signaling, even in absence of surface TCR. Importantly, TCR pathway genes were overexpressed in human T-ALL and mature T cell cancers and activation of TCR pathway kinases was STAT5 dependent. We confirmed STAT5 binding to these genes using ChIP-Seq analysis in human T-ALL cells, which were sensitive to pharmacologic inhibition by dual STAT3/5 degraders or ZAP70 tyrosine kinase blockers in vitro and in vivo. We provide genetic and biochemical proof that STAT5A and STAT5B hyperactivation can initiate T-ALL through TCR pathway hijacking and suggest similar mechanisms for other T cell cancers. Thus, STAT5 or TCR component blockade are targeted therapy options, particularly in patients with chemoresistant clones carrying [STAT5B.sup.N642H]., Introduction Acute lymphoblastic leukemia (ALL) is subdivided into B and T cell acute lymphoblastic leukemia (T-ALL), of which T-ALL represents up to 15% of pediatric and 25% of adult ALL [...]

BACKGROUND. The antituberculosis vaccine bacillus Calmette-Guerin (BCG) reduces overall infant mortality. Induction of innate immune memory, also termed trained immunity, contributes toward protection against heterologous infections. Since immune cells display oscillations in numbers and function throughout the day, we investigated the effect of BCG administration time on the induction of trained immunity. METHODS. Eighteen volunteers were vaccinated with BCG at 6 pm and compared with 36 age- and sex-matched volunteers vaccinated between 8 am and 9 am. Peripheral blood mononuclear cells were stimulated with Staphylococcus aureus and Mycobacterium tuberculosis before, as well as 2 weeks and 3 months after, BCG vaccination. Cytokine production was measured to assess the induction of trained immunity and adaptive responses, respectively. Additionally, the influence of vaccination time on induction of trained immunity was studied in an independent cohort of 302 individuals vaccinated between 8 am and 12 pm with BCG. RESULTS. Compared with evening vaccination, morning vaccination elicited both a stronger trained immunity and adaptive immune phenotype. In a large cohort of 302 volunteers, early morning vaccination resulted in a superior cytokine production capacity compared with later morning. A cellular, rather than soluble, substrate of the circadian effect of BCG vaccination was demonstrated by the enhanced capacity to induce trained immunity in vitro in morning- compared with evening-isolated monocytes. CONCLUSIONS. BCG vaccination in the morning induces stronger trained immunity and adaptive responses compared with evening vaccination. Future studies should take vaccine administration time into account when studying specific and nonspecific effects of vaccines; early morning should be the preferred moment of BCG administration. FUNDING. The Netherlands Organization for Scientific Research, the European Research Council, and the Danish National Research Foundation., Introduction The antituberculosis vaccine bacillus Calmette-Guerin (BCG) has the highest vaccine coverage worldwide (1). BCG protects primarily against disseminated tuberculosis (TB) in children (2), whereas protection against pulmonary TB in [...]

[FOXP3.sup.+] regulatory T cells ([T.sub.reg] cells) are abundant in the intestine, where they prevent dysregulated inflammatory responses to self and environmental stimuli. It is now appreciated that [T.sub.reg] cells acquire tissue-specific adaptations that facilitate their survival and function (1); however, key host factors controlling the [T.sub.reg] response in the intestine are poorly understood. The interleukin (IL)-1 family member IL-33 is constitutively expressed in epithelial cells at barrier sites (2), where it functions as an endogenous danger signal, or alarmin, in response to tissue damage (3). Recent studies in humans have described high levels of IL-33 in inflamed lesions of inflammatory bowel disease patients (4-7), suggesting a role for this cytokine in disease pathogenesis. In the intestine, both protective and pathological roles for IL-33 have been described in murine models of acute colitis (8-11), but its contribution to chronic inflammation remains ill defined. Here we show in mice that the IL-33 receptor ST2 is preferentially expressed on colonic [T.sub.reg] cells, where it promotes [T.sub.reg] function and adaptation to the inflammatory environment. IL-33 signalling in T cells stimulates [T.sub.reg] responses in several ways. First, it enhances transforming growth factor (TGF)-[β.sub.1]-mediated differentiation of [T.sub.reg] cells and, second, it provides a necessary signal for [T.sub.reg]-cell accumulation and maintenance in inflamed tissues. Strikingly, IL-23, a key pro-inflammatory cytokine in the pathogenesis of inflammatory bowel disease, restrained [T.sub.reg] responses through inhibition of IL-33 responsiveness. These results demonstrate a hitherto unrecognized link between an endogenous mediator of tissue damage and a major anti-inflammatory pathway, and suggest that the balance between IL-33 and IL-23 may be a key controller of intestinal immune responses., To identify potential tissue-specific modulators of colonic [T.sub.reg] cells, we compared the messenger RNA expression profiles of mesenteric lymph node and colonic [T.sub.reg] cells. We identified St2 (also known as [...]

IFNs [lambda]1, [lambda]2, and [lambda]3, or type III IFNs, are recently identified cytokines distantly related to type I IFNs. Despite an early evolutionary divergence, the 2 types of IFNs display similar antiviral activities, and both are produced primarily in dendritic cells. Although virus induction of the type I IFN-[beta] gene had served as a paradigm of gene regulation, relatively little is known about the regulation of IFN-[lambda] gene expression. Studies of virus induction of IFN-[lambda]1 identified an essential role of IFN regulatory factors (IRF) 3 and 7, which bind to a regulatory DNA sequence near the start site of transcription. Here, we report that the proximal promoter region of the IFN-[lambda]1 regulatory region is not sufficient for maximal gene induction in response to bacterial LPS, and we identify an essential cluster of homotypic NF-[kappa]B binding sites. Remarkably, these sites, which bind efficiently to NF-[kappa]B and function independently of the IRF3/7 binding sites, originate as transposable elements of the Alu and LTR families. We also show that depletion of the NF-[kappa]B RelA protein significantly reduces the level of the IFN-[lambda]1 gene expression. We conclude that IFN-[lambda]1 gene expression requires NF-[kappa]B, and we propose a model for IFN-[lambda]1 gene regulation, in which IRF and NF-[kapppa]B activate gene expression independently via spatially separated promoter elements. These observations provide insights into the independent evolution of the IFN-[lambda]1 and IFN-[beta] promoters and directly implicate transposable elements in the regulation of the IFN-[lambda]1 gene by NF-[kappa]B. gene regulation | interferon | transcription enhancer | NF-[kappa]B | Alu repeats

The adult human skin contains a vast number of T cells that are essential for skin homeostasis and pathogen defense. T cells are first observed in the skin at the early stages of gestation; however, our understanding of their contribution to early immunity has been limited by their low abundance and lack of comprehensive methodologies for their assessment. Here, we describe a new workflow for isolating and expanding significant amounts of T cells from fetal human skin. Using multiparametric flow cytometry and in situ immunofluorescence, we found a large population with a naive phenotype and small populations with a memory and regulatory phenotype. Their molecular state was characterized using single-cell transcriptomics and TCR repertoire profiling. Importantly, culture of total fetal skin biopsies facilitated T cell expansion without a substantial impact on their phenotype, a major prerequisite for subsequent functional assays. Collectively, our experimental approaches and data advance the understanding of fetal skin immunity and potential use in future therapeutic interventions. [ABSTRACT FROM AUTHOR]