Mystery at the heart of life

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December 21, 2014

Cell biology, Intelligent Design, News

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Cell biology
Intelligent Design
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By Biologic Institute’s Ann Gauger, at Christianity Today’s Behemoth, the secret life of cells:

Our bodies are made up of some 100 trillion cells. We tend to think of cells as static, because that’s how they were presented to us in textbooks. In fact, the cell is like the most antic, madcap, crowded (yet fantastically efficient) city you can picture. And at its heart lies a mystery—or I should say, several mysteries—involving three special kinds of molecules: DNA, RNA, and proteins.

These molecules are assembled into long chains called polymers, and are uniquely suited for the roles they play. More importantly, life absolutely depends upon them. We have to have DNA, RNA, and protein all present and active at the same time for a living organism to live.

How they work together so optimally and efficiently is not merely amazing, but also a great enigma, a mystery that lies at the heart of life itself. More. Paywall soon after. May be worth it.

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It is therefore likely that each tissue harbors a unique ILCP ‘‘repertoire’’ conditioned by environmental signals. It is remarkable that other uni-potent ILCPs were rarely detected in this organ, suggesting that at this stage of fetal development, the microenvironment may deliver signals that strongly polarize ILCPs toward ILC3s. Notch-mediated signaling has been proposed to play a role in directing lymphoid cell fate decisions, promoting the development of T-lineage primed precursors, as well as modifying ILCPs homeostasis [...]
Systemic Human ILC Precursors Provide a Substrate for Tissue ILC Differentiation. Lim AI, Li Y, Lopez-Lastra S, Stadhouders R, Paul F, Casrouge A, Serafini N, Puel A, Bustamante J, Surace L, Masse-Ranson G, David E, Strick-Marchand H, Le Bourhis L, Cocchi R, Topazio D, Graziano P, Muscarella LA, Rogge L, Norel X, Sallenave JM, Allez M, Graf T, Hendriks RW, Casanova JL, Amit I, Yssel H, Di Santo JP. Cell. 168(6):1086-1100.e10. doi: 10.1016/j.cell.2017.02.021.

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[...] ILCPs resemble naive T cells that can differentiate to diverse T helper subsets under appropriate environmental signals. [...] human ILCPs have signature TFs in a poised state that contrasts with the situation in naive T cells where these loci are actively repressed [...] [...] ILCPs expand extensively in the presence of cytokines, whereas naïve T cell homeostasis is primarily maintained through cytokine driven survival [...] [...] ILCPs appear to have some properties in common with naïve T cells, although a number of important differences exist that are consistent with their designation as immature progenitors.
Systemic Human ILC Precursors Provide a Substrate for Tissue ILC Differentiation. Lim AI1, Li Y2, Lopez-Lastra S3, Stadhouders R4, Paul F5, Casrouge A2, Serafini N2, Puel A6, Bustamante J6, Surace L2, Masse-Ranson G2, David E5, Strick-Marchand H2, Le Bourhis L7, Cocchi R8, Topazio D8, Graziano P8, Muscarella LA8, Rogge L9, Norel X10, Sallenave JM11, Allez M12, Graf T4, Hendriks RW13, Casanova JL14, Amit I5, Yssel H15, Di Santo JP16. Cell. 168(6):1086-1100.e10. doi: 10.1016/j.cell.2017.02.021.

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Innate lymphoid cells (ILCs) are a novel family of lymphoid effector cells that serve essential roles in the early immune response, comprising both ‘‘cytotoxic’’ ILCs (natural killer [NK] cells) and ‘‘helper’’ ILCs. Our identification of systemically distributed ILCPs suggests a model whereby circulating and tissue ILCPs provide a cellular substrate for ILC differentiation in situ in response to local environmental signals.
Systemic Human ILC Precursors Provide a Substrate for Tissue ILC Differentiation. Lim AI1, Li Y2, Lopez-Lastra S3, Stadhouders R4, Paul F5, Casrouge A2, Serafini N2, Puel A6, Bustamante J6, Surace L2, Masse-Ranson G2, David E5, Strick-Marchand H2, Le Bourhis L7, Cocchi R8, Topazio D8, Graziano P8, Muscarella LA8, Rogge L9, Norel X10, Sallenave JM11, Allez M12, Graf T4, Hendriks RW13, Casanova JL14, Amit I5, Yssel H15, Di Santo JP16. Cell. 168(6):1086-1100.e10. doi: 10.1016/j.cell.2017.02.021.

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Innate lymphoid cells (ILCs) represent innate versions of T helper and cytotoxic T cells that differentiate from committed ILC precursors (ILCPs). How ILCPs give rise to mature tissue-resident ILCs remains unclear. [...] diverse ILC subsets are generated in situ from systemically distributed ILCPs in response to local environmental signals.
Systemic Human ILC Precursors Provide a Substrate for Tissue ILC Differentiation. Lim AI1, Li Y2, Lopez-Lastra S3, Stadhouders R4, Paul F5, Casrouge A2, Serafini N2, Puel A6, Bustamante J6, Surace L2, Masse-Ranson G2, David E5, Strick-Marchand H2, Le Bourhis L7, Cocchi R8, Topazio D8, Graziano P8, Muscarella LA8, Rogge L9, Norel X10, Sallenave JM11, Allez M12, Graf T4, Hendriks RW13, Casanova JL14, Amit I5, Yssel H15, Di Santo JP16. Cell. 168(6):1086-1100.e10. doi: 10.1016/j.cell.2017.02.021.

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the cross-regulation of ILCs and T cells, involving DCs as a central platform of information exchange, needs to be deciphered by using new mouse models that allow targeting each cell type individually. [...] a role for ILCs beyond immunity, such as in the regulation of fat metabolism, needs to be unravelled in order to understand the integration of the immune system in host physiology.
Innate lymphoid cells: A new paradigm in immunology Gérard Eberl, Marco Colonna, James P. Di Santo, Andrew N. J. McKenzie Science Vol. 348, Issue 6237, aaa6566 DOI: 10.1126/science.aaa6566

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Much remains to be uncovered on the activation and function of ILCs. ILCs promptly translate signals produced by infected or injured tissues into effector cytokines that activate and regulate local innate and adaptive effector functions. Signals produced by the tissues activating ILCs include cytokines, and possibly also stress ligands and microbial compounds.
Innate lymphoid cells: A new paradigm in immunology Gérard Eberl, Marco Colonna, James P. Di Santo, Andrew N. J. McKenzie Science Vol. 348, Issue 6237, aaa6566 DOI: 10.1126/science.aaa6566

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The multiple facets of ILC development, activation, and function need to be further explored before efficient manipulation of ILCs can be achieved in the clinic. The developmental pathways leading to the different types of ILCs appear to be relatively complex, and modulation of these pathways by the microenvironment remains poorly understood, with questions remaining about ILC subset plasticity and stability. It will also be insightful to explore the development of ILCs not only during ontogeny, but also during evolution, in order to assess whether “cytotoxic” ILCs (NK cells) and “helper” ILCs (ILC1s, ILC2s, and ILC3s) served as a blueprint for the appearance of CD8+ cytotoxic and CD4+ TH cells
Innate lymphoid cells: A new paradigm in immunology Gérard Eberl, Marco Colonna, James P. Di Santo, Andrew N. J. McKenzie Science Vol. 348, Issue 6237, aaa6566 DOI: 10.1126/science.aaa6566

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A logical next step will be the identification of molecules that allow manipulation of ILCs and the orchestration of the optimal immune response after vaccination and immunotherapy—or in contrast, to block detrimental responses. The combination of a prompt activation of ILCs with both effector and regulatory functions, with the expansion of antigen-specific B and T cells, should lead to new and powerful avenues in clinical immunology.
Innate lymphoid cells: A new paradigm in immunology Gérard Eberl, Marco Colonna, James P. Di Santo, Andrew N. J. McKenzie Science Vol. 348, Issue 6237, aaa6566 DOI: 10.1126/science.aaa6566

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Innate lymphoid cells (ILCs) are a growing family of immune cells that mirror the phenotypes and functions of T cells. However, in contrast to T cells, ILCs do not express acquired antigen receptors or undergo clonal selection and expansion when stimulated. Instead, ILCs react promptly to signals from infected or injured tissues and produce an array of secreted proteins termed cytokines that direct the developing immune response into one that is adapted to the original insult. The complex cross-talk between microenvironment, ILCs, and adaptive immunity remains to be fully deciphered. Only by understanding these complex regulatory networks can the power of ILCs be controlled or unleashed in order to regulate or enhance immune responses in disease prevention and therapy.
Innate lymphoid cells: A new paradigm in immunology Gérard Eberl, Marco Colonna, James P. Di Santo, Andrew N. J. McKenzie Science Vol. 348, Issue 6237, aaa6566 DOI: 10.1126/science.aaa6566

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[...] being able to better associate long-range enhancers with gene targets would enhance the power of our approach considerably. [...] the interaction of enhancers and promoters is confined in topologically associated domains. [...] exploration of the chromatin organization of enhancer marks as well as the use of new computational methods should facilitate the assignment of enhancers to their targets. [...] future studies should aim to refine and resolve the transcriptional networks by incorporating these additional approaches.
Epigenetic landscapes reveal transcription factors that regulate CD8+ T cell differentiation Bingfei Yu, Kai Zhang, J Justin Milner, Clara Toma, Runqiang Chen, James P Scott-Browne, Renata M Pereira, Shane Crotty, John T Chang, Matthew E Pipkin, Wei Wang & Ananda W Goldrath Nature Immunology doi:10.1038/ni.3706

Work in progress... stay tuned. Complex complexity.Dionisio_{March 20, 2017
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Global investigation of TF-binding motifs using new approaches, such as protein-binding microarrays, might be beneficial in broadening the database of known TF-binding motifs. TFs function with co-factors to regulate specific gene expression; co-binding analyses could be incorporated into these analyses to improve our network construction.
Epigenetic landscapes reveal transcription factors that regulate CD8+ T cell differentiation Bingfei Yu, Kai Zhang, J Justin Milner, Clara Toma, Runqiang Chen, James P Scott-Browne, Renata M Pereira, Shane Crotty, John T Chang, Matthew E Pipkin, Wei Wang & Ananda W Goldrath Nature Immunology doi:10.1038/ni.3706

Work in progress... stay tuned. Complex complexity.Dionisio_{March 20, 2017
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Treatment with dexamethasone increased the proportion of MP subset during differentiation, which demonstrated a previously unknown role for glucocorticoid hormones in modulating CD8+ T cell differentiation and a potential strategy for manipulating memory-cell differentiation.
Epigenetic landscapes reveal transcription factors that regulate CD8+ T cell differentiation Bingfei Yu, Kai Zhang, J Justin Milner, Clara Toma, Runqiang Chen, James P Scott-Browne, Renata M Pereira, Shane Crotty, John T Chang, Matthew E Pipkin, Wei Wang & Ananda W Goldrath Nature Immunology doi:10.1038/ni.3706

Work in progress... stay tuned. Complex complexity.Dionisio_{March 20, 2017
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How YY1 regulates differentiation of the TE subset and if YY1 controls chromatin interactions in the TE subset remain to be determined.
Epigenetic landscapes reveal transcription factors that regulate CD8+ T cell differentiation Bingfei Yu, Kai Zhang, J Justin Milner, Clara Toma, Runqiang Chen, James P Scott-Browne, Renata M Pereira, Shane Crotty, John T Chang, Matthew E Pipkin, Wei Wang & Ananda W Goldrath Nature Immunology doi:10.1038/ni.3706

Work in progress... stay tuned. Complex complexity.Dionisio_{March 20, 2017
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[...] it is essential to develop new methods that rank the potential importance of TFs on the basis of the quantity and quality of the TF-regulated genes. Future modifications of gene weights by gene ontology could facilitate identification of TFs important in specific functions or pathways.
Epigenetic landscapes reveal transcription factors that regulate CD8+ T cell differentiation Bingfei Yu, Kai Zhang, J Justin Milner, Clara Toma, Runqiang Chen, James P Scott-Browne, Renata M Pereira, Shane Crotty, John T Chang, Matthew E Pipkin, Wei Wang & Ananda W Goldrath Nature Immunology doi:10.1038/ni.3706

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[...] the identification of relevant TFs exclusively on the basis of gene-expression analysis provides only partial understanding of the TF networks involved. [...] gene expression alone could not fully explain the mechanisms behind cell-fate determination and supported the idea that the binding of TFs and gene expression should be considered together to facilitate the identification of important TFs. Differential TF binding can be achieved via numerous mechanisms, including variable chromatin state and accessibility, TF localization, the availability of co-factors, and post-translational modification of TFs.
Epigenetic landscapes reveal transcription factors that regulate CD8+ T cell differentiation Bingfei Yu, Kai Zhang, J Justin Milner, Clara Toma, Runqiang Chen, James P Scott-Browne, Renata M Pereira, Shane Crotty, John T Chang, Matthew E Pipkin, Wei Wang & Ananda W Goldrath Nature Immunology doi:10.1038/ni.3706

Work in progress... stay tuned. Complex complexity.Dionisio_{March 20, 2017
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This analysis suggested a previously unknown function for T-bet in maintaining the accumulation of MP cells, potentially through regulation of the anti-apoptotic protein Bcl-2 and additional targets. Studies of distinct targets will further elucidate nuanced functions of T-bet in driving effector and memory fates.
Epigenetic landscapes reveal transcription factors that regulate CD8+ T cell differentiation Bingfei Yu, Kai Zhang, J Justin Milner, Clara Toma, Runqiang Chen, James P Scott-Browne, Renata M Pereira, Shane Crotty, John T Chang, Matthew E Pipkin, Wei Wang & Ananda W Goldrath Nature Immunology doi:10.1038/ni.3706

Work in progress... stay tuned. Complex complexity.Dionisio_{March 20, 2017
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The function and differentiation state of immune cells are controlled by TFs that relay environmental cues through regulation of gene expression. Efficient transcriptional regulation requires interaction between TFs and chromatin remodelers to control the binding of TFs with high fidelity. Key information is encoded in regulatory elements that contain TF-binding sequences and are associated with specific histone modifications that influence the accessibility, structure and location of those elements.
Epigenetic landscapes reveal transcription factors that regulate CD8+ T cell differentiation Bingfei Yu, Kai Zhang, J Justin Milner, Clara Toma, Runqiang Chen, James P Scott-Browne, Renata M Pereira, Shane Crotty, John T Chang, Matthew E Pipkin, Wei Wang & Ananda W Goldrath Nature Immunology doi:10.1038/ni.3706

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In response to infection, naive CD8+ T cells differentiate into a heterogeneous population of pathogen-specific effector CD8+ T cells. While the majority of these T cells undergo apoptosis after resolution of the infection, a small fraction persists as memory cells and provide lasting protection against re-infection.
Epigenetic landscapes reveal transcription factors that regulate CD8+ T cell differentiation Bingfei Yu, Kai Zhang, J Justin Milner, Clara Toma, Runqiang Chen, James P Scott-Browne, Renata M Pereira, Shane Crotty, John T Chang, Matthew E Pipkin, Wei Wang & Ananda W Goldrath Nature Immunology doi:10.1038/ni.3706

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Dynamic changes in the expression of transcription factors (TFs) can influence the specification of distinct CD8+ T cell fates, but the observation of equivalent expression of TFs among differentially fated precursor cells suggests additional underlying mechanisms. Our data define the epigenetic landscape of differentiation intermediates and facilitate the identification of TFs with previously unappreciated roles in CD8+ T cell differentiation.
Epigenetic landscapes reveal transcription factors that regulate CD8+ T cell differentiation Bingfei Yu, Kai Zhang, J Justin Milner, Clara Toma, Runqiang Chen, James P Scott-Browne, Renata M Pereira, Shane Crotty, John T Chang, Matthew E Pipkin, Wei Wang & Ananda W Goldrath Nature Immunology doi:10.1038/ni.3706

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[...] as most transcription factors are used in both innate and adaptive lineages, unique combinations of factors could result in innate vs. adaptive lineage choice. Uncovering the factors and mechanisms that specify innate versus adaptive fates during early development is a fascinating and challenging new issue. The ongoing identification of early intermediate stages between lymphoid progenitors and ILCs should eventually allow these questions to be addressed.
A doppelgänger of T cell development Christelle Harly & Avinash Bhandoola Editorials: Cell Cycle Features http://dx.doi.org/10.1080/15384101.2015.1125244 Journal Cell Cycle ? Volume 15, 2016 – Issue 4

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Innate lymphoid cells (ILCs) were recently identified as the innate counterpart of adaptive T-cells, after the discovery of several ILC subsets with effector functions strikingly similar to T-cell subsets. Although our understanding of ILCs is still preliminary, it is becoming clear that transcriptional programs controlling ILC terminal differentiation and effector functions closely mirror those of conventional ?? T-cells [...]
A doppelgänger of T cell development Christelle Harly & Avinash Bhandoola Editorials: Cell Cycle Features http://dx.doi.org/10.1080/15384101.2015.1125244 Journal Cell Cycle ? Volume 15, 2016 - Issue 4

Did somebody say “programs”? ???? Complex complexity.Dionisio_{March 17, 2017
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CD8 T cell memory is characterized by rapid recall of effector function, increased proliferation, and reduced activation requirements. Despite the extensive functional characterization, the molecular mechanisms that facilitate these enhanced properties are not well characterized. [...] memory CD8 T cells display a preprogrammed chromatin accessibility profile and maintain a molecular history of cis-element usage, thereby reducing the steps necessary to revive effector functions.
Cutting Edge: Chromatin Accessibility Programs CD8 T Cell Memory. Scharer CD, Bally AP, Gandham B, Boss JM J Immunol. 198(6):2238-2243. doi: 10.4049/jimmunol.1602086

[Emphasis added] Did somebody say "preprogrammed"? :) Complex complexity.Dionisio_{March 17, 2017
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The discovery of diverse ILC subsets represents a major advance in our understanding of how immune responses are established in order to cope with infection, inflammation and tissue repair. Deciphering the signals that promote ILC subset development and regulate their peripheral function will be key to understanding the balance between these outcomes.
Transcriptional regulation of innate lymphoid cell fate Nicolas Serafini, Christian A. J. Vosshenrich & James P. Di Santo Nature Reviews Immunology 15, 415–428 doi:10.1038/nri3855

Work in progress… stay tuned. Complex complexity.Dionisio_{March 16, 2017
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‘Plasticity’ describes how differentiated cells can acquire new characteristics (for example, phenotypes and functions) depending on the environment. A role for epigenetic modifications in this process is likely but has not yet been established.
Transcriptional regulation of innate lymphoid cell fate Nicolas Serafini, Christian A. J. Vosshenrich & James P. Di Santo Nature Reviews Immunology 15, 415–428 doi:10.1038/nri3855

Work in progress… stay tuned. Complex complexity.Dionisio_{March 16, 2017
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Lymphocyte lifespan can vary enormously in different cell types, from several days to the host’s lifetime. We have little information on lifespan for other ILC subsets, and additional work is needed to answer this question. [...] it will be interesting to study whether these expanded ILCs have ‘memory’ properties.
Transcriptional regulation of innate lymphoid cell fate Nicolas Serafini, Christian A. J. Vosshenrich & James P. Di Santo Nature Reviews Immunology 15, 415–428 doi:10.1038/nri3855

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Whether inflammatory ILC2s are an obligate intermediate in ILC2 differentiation under non-inflammatory conditions requires further study. Considering the close relationship between Notch, TCF1 and BCL11B, it is possible that the latter is also involved in ILC2 development. The factors that induce ROR? in the ILC2 lineage are not known [...] The downstream targets of ROR? that promote ILC2 differentiation are similarly undefined. [...] putative precursors for EOMES?ILC1s and for ILC2s have been proposed9,35; however, it is not clear to what extent these are true precursors or simply mature ILCs in the ‘resting’ state. Cytokines of the common ?-chain (?c) family are essential for the development of all known ILC subsets. [...] It remains unclear at what stage these cytokines exert their effects on ILC homeostasis. The role of T cell-derived IL?2 as a generic modifier of ILC homeostasis and the ability of regulatory T cells to indirectly inhibit this process provide an additional mechanism for control of ILC homeostasis.
Transcriptional regulation of innate lymphoid cell fate Nicolas Serafini, Christian A. J. Vosshenrich & James P. Di Santo Nature Reviews Immunology 15, 415–428 doi:10.1038/nri3855

Work in progress… stay tuned. Complex complexity.Dionisio_{March 16, 2017
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[...] NFIL3 seems to be an important orchestrator of ILCP emergence from CLPs. More work is required to understand how NFIL3 expression is controlled and to determine the relevant NFIL3 targets in CLPs and ILCPs. An in?depth characterization of CILCPs in GATA3?deficient mice may provide answers. [...] whether ILCPs should be considered to be ‘innate’ versions of naive T cells is not clear. Whether these soluble factors and their associated STAT pathways are involved in early stages of ILC1 commitment from ILCPs is not known. Eomes- and Tbx21-reporter mice will be important tools for identifying ILC1 precursors in future studies. Upstream regulators of ETS1 in lymphoid precursors are poorly characterized [...]
Transcriptional regulation of innate lymphoid cell fate Nicolas Serafini, Christian A. J. Vosshenrich & James P. Di Santo Nature Reviews Immunology 15, 415–428 doi:10.1038/nri3855

Work in progress… stay tuned. Complex complexity.Dionisio_{March 16, 2017
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Innate lymphoid cells (ILCs) are a recently described family of lymphoid effector cells that have important roles in immune defence, inflammation and tissue remodelling. Our knowledge of the signals and mechanisms that regulate ILC differentiation from haematopoietic precursors is still in its infancy. [...] the range of functional abilities of different ILC groups is not fully appreciated, leaving room for further refinement (and possible redefinition) of the ILC nomenclature. A better understanding of the critical stages and regulators of ILC differentiation could eventually lead to new experimental or therapeutic approaches for manipulating the immune system in the early stages of pathogenic infection or during inflammatory disease.
Transcriptional regulation of innate lymphoid cell fate Nicolas Serafini, Christian A. J. Vosshenrich & James P. Di Santo Nature Reviews Immunology 15, 415–428 doi:10.1038/nri3855

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[...] the regulatory effects of Ikaros on ILC3 development and function are stage specific. [...] it is unclear whether some ILC1s may express or have expressed Eomes during their development. Transcriptional regulation underlies the functional actions of various lymphoid effectors and is the key to further understanding how the immune system works. [...] more comprehensive studies are still required to understand how recently identified ILC populations are generated and how their functions are controlled. [...] there are still many challenges to address in order to understand how ILCs and ILC-functions are ultimately regulated and controlled.
Transcriptional regulators dictate innate lymphoid cell fates. Zhong C, Zhu J Protein Cell. doi: 10.1007/s13238-017-0369-7.

[emphasis added] Work in progress… stay tuned. Complex complexity.Dionisio_{March 16, 2017
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Retinoic acid (RA) is the active metabolite of Vitamin A, which activates the nuclear receptors retinoic acid receptor (RAR) or retinoid X receptor (RXR). Maternal retinoid level is thus required for setting up immune structures in the offspring.
Transcriptional regulators dictate innate lymphoid cell fates. Zhong C, Zhu J Protein Cell. doi: 10.1007/s13238-017-0369-7.

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