Natural killer (NK) cells play critical roles defending against tumors and pathogens. We show that mice lacking both transcription factors Eomesodermin (Eomes) and T-bet failed to develop NK cells. ...Developmental stability of immature NK cells constitutively expressing the death ligand TRAIL depended on T-bet. Conversely, maturation characterized by loss of constitutive TRAIL expression and induction of Ly49 receptor diversity and integrin CD49b (DX5
+) required Eomes. Mature NK cells from which Eomes was deleted reverted to phenotypic immaturity if T-bet was present or downregulated NK lineage antigens if T-bet was absent, despite retaining expression of Ly49 receptors. Fetal and adult hepatic hematopoiesis restricted Eomes expression and limited NK development to the T-bet-dependent, immature stage, whereas medullary hematopoiesis permitted Eomes-dependent NK maturation in adult mice. These findings reveal two sequential, genetically separable checkpoints of NK cell maturation, the progression of which is metered largely by the anatomic localization of hematopoiesis.
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► NK cells are absent in mice lacking both T-bet and Eomes ► T-bet is essential to stabilize immature, TRAIL
+ NK cells ► Eomes is required to develop and partially maintain mature, DX5
+ NK cells ► NK cells lose NK antigens after deletion of T-bet and Eomes
How intestinal microbes regulate metabolic syndrome is incompletely understood. We show that intestinal microbiota protects against development of obesity, metabolic syndrome, and pre-diabetic ...phenotypes by inducing commensal-specific Th17 cells. High-fat, high-sugar diet promoted metabolic disease by depleting Th17-inducing microbes, and recovery of commensal Th17 cells restored protection. Microbiota-induced Th17 cells afforded protection by regulating lipid absorption across intestinal epithelium in an IL-17-dependent manner. Diet-induced loss of protective Th17 cells was mediated by the presence of sugar. Eliminating sugar from high-fat diets protected mice from obesity and metabolic syndrome in a manner dependent on commensal-specific Th17 cells. Sugar and ILC3 promoted outgrowth of Faecalibaculum rodentium that displaced Th17-inducing microbiota. These results define dietary and microbiota factors posing risk for metabolic syndrome. They also define a microbiota-dependent mechanism for immuno-pathogenicity of dietary sugar and highlight an elaborate interaction between diet, microbiota, and intestinal immunity in regulation of metabolic disorders.
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•Commensal-induced Th17 cells regulate epithelial lipid absorption•Sugar and ILC3 increase Faecalibaculum rodentium to displace Th17-inducing bacteria•Microbiota-induced Th17 cells protect from diet-induced obesity and metabolic disease•Sugar eliminates commensal Th17 cells to increase the risk for metabolic disease
Sugar in mouse diets promotes metabolic disease by upsetting the gut microbial balance and driving loss of the Th17 cells that regulate lipid absorption by the intestinal epithelium.
In mammals, helper T cells orchestrate defense against diverse pathogens. However, these warriors of the immune system can also result in self-inflicted injury culminating in autoimmune and allergic ...diseases. Recent findings—such as the discovery of the Th17 lineage—have revealed additional complexity in the fates chosen by helper T cells and have begun to reshape our view of how signaling and transcriptional networks generate appropriate and inappropriate immunity.
Metazoan sibling cells often diverge in activity and identity, suggesting links between growth signals and cell fate. We show that unequal transduction of nutrient-sensitive PI3K/AKT/mTOR signaling ...during cell division bifurcates transcriptional networks and fates of kindred cells. A sibling B lymphocyte with stronger signaling, indexed by FoxO1 inactivation and IRF4 induction, undergoes PI3K-driven Pax5 repression and plasma cell determination, while its sibling with weaker PI3K activity renews a memory or germinal center B cell fate. PI3K-driven effector T cell determination silences TCF1 in one sibling cell, while its PI3K-attenuated sibling self-renews in tandem. Prior to bifurcations achieving irreversible plasma or effector cell fate determination, asymmetric signaling during initial divisions specifies a more proliferative, differentiation-prone lymphocyte in tandem with a more quiescent memory cell sibling. By triggering cell division but transmitting unequal intensity between sibling cells, nutrient-sensitive signaling may be a frequent arbiter of cell fate bifurcations during development and repair.
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•Plasma cells and effector T cells are produced during an asymmetric cell division•Production of differentiated lymphocytes is coupled to renewal of the progenitor cell•Unequal PI3K signaling during cell division bifurcates sibling fates•Unequal PI3K/AKT/mTOR intensity causes unequal FoxO1 inactivation in sibling cells
Stem cells paradoxically produce differentiated progeny while re-producing themselves. Lin et al. use direct examination of sibling cell pairs completing their division to show that unequal transmission of PI3K signal transduction causes one cell to differentiate while its sister cell remains pluripotent.
Heightened immunity after a primary infection, persistent control of low-level infection, or vanquished immunity from chronic-active infection and cancer are interrelated issues concerning the nature ...of T-cell regeneration during immunity. For many regenerating tissues and cellular systems, such as epithelia and blood, there are at least three distinguishable stages of development and repair, marked by progressive loss of self-renewal and progressive commitment to differentiation. T cells seem to be no different. Quiescent precursors become activated and yield anabolic, proliferative progenitors while self-renewing the quiescent precursor population. Activated progenitors then yield differentiated cellular descendants alongside the self-renewal of progenitors. Nomenclature reflecting the mutually opposing nature of T-cell self-renewal and T-cell differentiation would help synchronize phenomena such as T-cell memory, protective immunity, and T-cell exhaustion with other regenerative paradigms, as well as offer new strategies to influence the intensity and duration of immunity.
Intratumoral (IT) STING activation results in tumor regression in preclinical models, yet factors dictating the balance between innate and adaptive anti-tumor immunity are unclear. Here, clinical ...candidate STING agonist ADU-S100 (S100) is used in an IT dosing regimen optimized for adaptive immunity to uncover requirements for a T cell-driven response compatible with checkpoint inhibitors (CPIs). In contrast to high-dose tumor ablative regimens that result in systemic S100 distribution, low-dose immunogenic regimens induce local activation of tumor-specific CD8+ effector T cells that are responsible for durable anti-tumor immunity and can be enhanced with CPIs. Both hematopoietic cell STING expression and signaling through IFNAR are required for tumor-specific T cell activation, and in the context of optimized T cell responses, TNFα is dispensable for tumor control. In a poorly immunogenic model, S100 combined with CPIs generates a survival benefit and durable protection. These results provide fundamental mechanistic insights into STING-induced anti-tumor immunity.
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•Dose of intratumoral STING agonist dictates expansion of tumor-specific T cells•Lower immunogenic dosing regimens elicit durable tumor control via CD8+ T cells•Higher tumor ablative dosing regimens compromise durable anti-tumor immunity•Immunogenic dosing is ideal for checkpoint inhibitor combination therapy
Intratumoral STING pathway activation is a promising therapeutic approach to treat cancer. While high doses of STING agonist are effective at clearing injected tumors, Sivick et al. find that lower doses of STING agonist are optimal for generating robust systemic tumor-specific T cell responses and durable anti-tumor immunity.
The cellular progeny of a clonally selected lymphocyte must execute function. However, their function must often occur in more than one way, in more than one place and at more than one time. ...Experimental evidence supports the view that a single activated lymphocyte can produce a variety of cellular descendants. The mechanisms that are responsible for generating diversity among the progeny of a single lymphocyte remain a subject of lively controversy. Some groups have suggested stochastic mechanisms that are analogous to the diversification of the antigen receptor repertoire. We suggest that the complexity of lymphocyte fates in space and time can be derived from a single naive lymphocyte using the principles of cell diversification that are common in developmental and regenerative biology, including (but not limited to) asymmetric cell division.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Polarized segregation of proteins in T cells is thought to play a role in diverse cellular functions including signal transduction, migration, and directed secretion of cytokines. Persistence of this ...polarization can result in asymmetric segregation of fate-determining proteins during cell division, which may enable a T cell to generate diverse progeny. Here, we provide evidence that a lineage-determining transcription factor, T-bet, underwent asymmetric organization in activated T cells preparing to divide and that it was unequally partitioned into the two daughter cells. This unequal acquisition of T-bet appeared to result from its asymmetric destruction during mitosis by virtue of concomitant asymmetric segregation of the proteasome. These results suggest a mechanism by which a cell may unequally localize cellular activities during division, thereby imparting disparity in the abundance of cell fate regulators in the daughter cells.
► A dividing T cell unequally apportions T-bet to its daughter cells ► Localized destruction of T-bet occurs in the setting of proteasome asymmetry ► Phosphorylation of T-bet is critical for its degradation and asymmetry ► Inhibiting proteasome activity or asymmetry prevents unequal T-bet partitioning
Interferon-γ (IFN-γ) promotes a population of T-bet+ CXCR3+ regulatory T (Treg) cells that limit T helper 1 (Th1) cell-mediated pathology. Our studies demonstrate that interleukin-27 (IL-27) also ...promoted expression of T-bet and CXCR3 in Treg cells. During infection with Toxoplasma gondii, a similar population emerged that limited T cell responses and was dependent on IFN-γ in the periphery but on IL-27 at mucosal sites. Transfer of Treg cells ameliorated the infection-induced pathology observed in Il27−/− mice, and this was dependent on their ability to produce IL-10. Microarray analysis revealed that Treg cells exposed to either IFN-γ or IL-27 have distinct transcriptional profiles. Thus, IFN-γ and IL-27 have different roles in Treg cell biology and IL-27 is a key cytokine that promotes the development of Treg cells specialized to control Th1 cell-mediated immunity at local sites of inflammation.
► IL-27 promotes Treg cells that express T-bet, CXCR3, and IL-10 ► Treg cells prevent infection-induced immune pathology in Il27−/− mice ► IL-27 and IFN-γ have distinct effects on Treg cell biology at local and peripheral sites
T follicular helper (Tfh) cells express transcription factor BCL-6 and cytokine IL-21. Mature Tfh cells are also capable of producing IFN-γ without expressing the Th1 transcription factor T-bet. ...Whether this IFN-γ-producing Tfh population represents a unique Tfh subset with a distinct differentiation pathway is poorly understood. By using T-bet fate-mapping mouse strains, we discovered that almost all the IFN-γ-producing Tfh cells have previously expressed T-bet and express high levels of NKG2D. DNase I hypersensitivity analysis indicated that the
gene locus is partially accessible in this "ex-T-bet" population with a history of T-bet expression. Furthermore, multicolor tissue imaging revealed that the ex-T-bet Tfh cells found in germinal centers express IFN-γ in situ. Finally, we found that IFN-γ-expressing Tfh cells are absent in T-bet-deficient mice, but fully present in mice with T-bet deletion at late stages of T cell differentiation. Together, our findings demonstrate that transient expression of T-bet epigenetically imprints the
locus for cytokine production in this Th1-like Tfh cell subset.
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