Early innate lymphoid progenitors (EILPs) have recently been identified in mouse adult bone marrow as a multipotential progenitor population specified toward innate lymphoid cell (ILC) lineages, but ...their relationship with other described ILC progenitors is still unclear. In this study, we examine the progenitor-successor relationships between EILPs, all-lymphoid progenitors (ALPs), and ILC precursors (ILCps). Functional, bioinformatic, phenotypical, and genetic approaches collectively establish EILPs as an intermediate progenitor between ALPs and ILCps. Our work additionally provides new candidate regulators of ILC development and clearly defines the stage of requirement of transcription factors key for early ILC development.
Innate lymphoid cells (ILCs) play important functions in immunity and tissue homeostasis, but their development is poorly understood. Through the use of single-cell approaches, we examined the ...transcriptional and functional heterogeneity of ILC progenitors, and studied the precursor-product relationships that link the subsets identified. This analysis identified two successive stages of ILC development within T cell factor 1-positive (TCF-1
) early innate lymphoid progenitors (EILPs), which we named 'specified EILPs' and 'committed EILPs'. Specified EILPs generated dendritic cells, whereas this potential was greatly decreased in committed EILPs. TCF-1 was dispensable for the generation of specified EILPs, but required for the generation of committed EILPs. TCF-1 used a pre-existing regulatory landscape established in upstream lymphoid precursors to bind chromatin in EILPs. Our results provide insight into the mechanisms by which TCF-1 promotes developmental progression of ILC precursors, while constraining their dendritic cell lineage potential and enforcing commitment to ILC fate.
Interactions between thymic epithelial cells (TEC) and developing thymocytes are essential for T cell development, but molecular insights on TEC and thymus homeostasis are still lacking. Here we ...identify distinct transcriptional programs of TEC that account for their age-specific properties, including proliferation rates, engraftability and function. Further analyses identify Myc as a regulator of fetal thymus development to support the rapid increase of thymus size during fetal life. Enforced Myc expression in TEC induces the prolonged maintenance of a fetal-specific transcriptional program, which in turn extends the growth phase of the thymus and enhances thymic output; meanwhile, inducible expression of Myc in adult TEC similarly promotes thymic growth. Mechanistically, this Myc function is associated with enhanced ribosomal biogenesis in TEC. Our study thus identifies age-specific transcriptional programs in TEC, and establishes that Myc controls thymus size.
The transcription factor TCF-1 (encoded by
) plays critical roles in several lineages of hematopoietic cells. In this study, we examined the molecular basis for
regulation in T cells, innate lymphoid ...cells, and migratory conventional dendritic cells that we find express
. We identified a 1 kb regulatory element crucial for the initiation of
expression in T cells and innate lymphoid cells, but dispensable for
expression in
-expressing dendritic cells. Within this region, we identified a Notch binding site important for the initiation of
expression in T cells but not in innate lymphoid cells. Our work establishes that the same regulatory element is used by distinct transcriptional controllers to initiate
expression in T cells and ILCs.
Human γδ T cells comprise a first line of defense through T-cell receptor (TCR) recognition of stressed cells. However, the molecular determinants and stress pathways involved in this recognition are ...largely unknown. Here we show that exposure of tumor cells to various stress situations led to tumor cell recognition by a Vγ8Vδ3 TCR. Using a strategy that we previously developed to identify antigenic ligands of γδ TCRs, annexin A2 was identified as the direct ligand of Vγ8Vδ3 TCR, and was found to be expressed on tumor cells upon the stress situations tested in a reactive oxygen species-dependent manner. Moreover, purified annexin A2 was able to stimulate the proliferation of a Vδ2neg γδ T-cell subset within peripheral blood mononuclear cells and other annexin A2-specific Vδ2neg γδ T-cell clones could be derived from peripheral blood mononuclear cells. We thus propose membrane exposure of annexin A2 as an oxidative stress signal for some Vδ2neg γδ T cells that could be involved in an adaptive stress surveillance.
T follicular helper (TFH) and T helper 1 (Th1) cells generated after viral infections are critical for the control of infection and the development of immunological memory. However, the mechanisms ...that govern the differentiation and maintenance of these two distinct lineages during viral infection remain unclear. We found that viral-specific TFH and Th1 cells showed reciprocal expression of the transcriptions factors TCF1 and Blimp1 early after infection, even before the differential expression of the canonical TFH marker CXCR5. Furthermore, TCF1 was intrinsically required for the TFH cell response to viral infection; in the absence of TCF1, the TFH cell response was severely compromised, and the remaining TCF1-deficient TFH cells failed to maintain TFH-associated transcriptional and metabolic signatures, which were distinct from those in Th1 cells. Mechanistically, TCF1 functioned through forming negative feedback loops with IL-2 and Blimp1. Our findings demonstrate an essential role of TCF1 in TFH cell responses to viral infection.
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•TCF1 and Blimp1 are reciprocally expressed in viral-specific TFH and Th1 cells•TCF1 is intrinsically required for viral-specific TFH cell responses•TCF1 forms negative feedback loops with IL-2 and Blimp1•TCF1 maintains the transcriptional and metabolic signatures of TFH cells
TFH cells are critical for long-term humoral responses. Wu et al. examine the molecular mechanisms that govern the choice of activated CD4 T cells between TFH and Th1 fates, and they find that the transcription factor TCF1 promotes viral-specific TFH cell responses through a negative feedback loop with IL-2 and Blimp1.
Despite significant advances, the eradication of cancer remains a clinical challenge which justifies the urgent exploration of additional therapeutic strategies such as immunotherapies. Human ...peripheral Vγ9Vδ2 T cells represent an attractive candidate subset for designing safe, feasible and effective adoptive T cell transfer-based therapies. However, following their infiltration within tumors, γδ T cells are exposed to various regulating constituents and signals from the tumor microenvironment (TME), which severely alter their antitumor functions. Here, we show that TGF-β, whose elevated production in some solid tumors is linked to a poor prognosis, interferes with the antigenic activation of human Vγ9Vδ2 T cells
. This regulatory cytokine strongly impairs their cytolytic activity, which is accompanied by the induction of particular phenotypic, transcriptomic and metabolic changes. Collectively, these observations provide information for better understanding and targeting the impact of TME components to regulate the antitumor activity of human T cell effectors.
To land on a surface the bat needs to get a grip with their tiny feet, which are interconnected to the wings via the inner wing membrane (the plagiopatagium) and therefore quite immobile. Because the ...bat has to slow down just before initiating the somersault, this prevents the use of aerodynamic forces–these are small anyway at such low speeds, and the proximity to the landing site prevents vigorous flapping. The transgenic LUSHD118A did not result in the enhanced OSN activity that Laughlin et al. had observed in the infusion experiment. ...these neurons retained the ability to be activated by cVA, and lush mutant flies expressing additional LUSH mutant proteins at endogenous levels didn’t recapitulate the increased or decreased cVA sensitivity shown by Laughlin et al. ...the authors show that multicellular organisms comprising these high-mutation cells are less fit. ...their experiments not only provide valuable insight into ancient evolutionary transitions to multicellularity but may also guide studies of reversion to unicellularity, whereby cancerous cells arise by flouting rules governing replication or quiescence in multicellular organisms. First some background: since roughly the 1970s, various government authorities have required that research proposing to use nonhuman animals undergo an independent review and approval process before it is conducted.
Switch hitter: Bcl11b in T cells and ILC2s Harly, Christelle; Bhandoola, Avinash
The Journal of experimental medicine,
2020-Jan-06, Letnik:
217, Številka:
1
Journal Article
Recenzirano
Odprti dostop
In this issue of JEM, Hosokawa et al. (https://doi.org/10.1084/jem.20190972) establish that transcription factor Bcl11b regulates almost completely distinct sets of genes in T cell precursors and ...ILC2s. To understand how this occurs, they identify multiple levels of functional regulation for Bcl11b that are used differently by T cell precursors and ILC2s.
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