James P. Di Santo

Staying innate: transcription factor maintenance of innate lymphoid cell identity

Author’s addresses James P. Di Santo1,2 1 Innate Immunity Unit, Institut Pasteur, Paris, France. 2 Inserm U668, Institut Pasteur, Paris, France.

Summary: Innate and adaptive lymphocytes are characterized by phenotypic and functional characteristics that result from genomic rearrangements (in the case of antigen-specific B and T cells) coupled with selective gene expression patterns that are generated in a contextdependent fashion. Cell-intrinsic expression of transcription factors (TFs) play a critical role in the regulation of gene expression that establish the distinct lymphoid subsets but also have been proposed to play an ongoing role in the maintenance of lineage-associated transcriptional signatures that comprise lymphocyte identity. This is the case for CD19+ B cells that require Pax5 expression throughout their lifespan, as well as for diverse T-helper subsets that have specialized immune functions. Innate lymphoid cells (ILCs) comprise diverse effectors cells that differentiate under TF control and have critical roles in the early stages of immune responses. In this review, ILC development is reviewed and the requirement for persistent TF expression in the maintenance of transcriptional signatures that define ILC identity is explored.

Correspondence to: James P. Di Santo Innate Immunity Unit Institut Pasteur 25 rue du Docteur Roux 75724 Paris, France Tel.: + 33 1 45 68 86 96 Fax: + 33 1 40 61 35 10 e-mail: [email protected] Acknowledgements I thank members of the Innate Immunity Unit for discussions and insightful comments on ILC biology. Study in the Innate Immunity Unit is supported by Institut Pasteur, the Institut National de la Sante et de la Recherche Medicale (INSERM), LNCC (Equipe Labellisee Ligue Contre le Cancer), and the Agence National pour la Recherche (Program ‘Blanc’ Gut_ILC). The author declares no financial or commercial conflict of interest.

This article is part of a series of reviews covering Transcriptional and Epigenetic Networks Orchestrating Immune Cell Development and Function appearing in Volume 261 of Immunological Reviews.

Immunological Reviews 2014 Vol. 261: 169–176 Printed in Singapore. All rights reserved

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Immunological Reviews 0105-2896

Keywords: innate, lymphocyte, transcription factor, development

Introduction Lymphopoiesis describes the process that generates mature lymphocytes from multi-potent hematopoietic precursors, including hematopoietic stem cells. Lymphocyte development involves the progressive shedding of alternative (nonlymphoid) hematopoietic cell fates in developing precursors, resulting in the formation of progenitor cells that have restricted potential to generate innate and adaptive lymphocytes. The common lymphoid progenitor (CLP) represents one well-defined lymphoid-restricted hematopoietic precursor population that has the capacity to develop into adaptive B and T cells as well as a series of innate lymphocytes, including natural killer (NK) cells and other innate lymphoid cells (ILCs) (1, 2). Comparison of the transcriptional profiles of CLPs with other lineage-restricted progenitors (of the myeloid and erythroid lineages) has helped to identify critical genes that control the process of lymphopoiesis (3).

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Immunological Reviews 261/2014


Di Santo  Transcriptional signatures and ILC identity

Included among these differentially expressed mRNAs are a series of transcription factors (TFs), including Ikaros, E2A, PU.1, and Gfi1, that critically regulate gene expression and promote lymphopoiesis through lymphoid ‘priming’ of multi-potent progenitors (4, 5). The role for these regulators in the generation of CLPs is not being further discussed here, and the readers are referred to an excellent review on this subject (6). The activity of these TFs includes not only positive transcriptional activation of lymphoid-restricted gene programs [including expression of the interleukin-7 receptor-a (IL-7Ra) and recombinase activating genes (Rags)] but also negative transcriptional repression of other cell fates. A combined feed-forward mechanism coupled with strong restriction of alternative options results in a critical focusing of cell differentiation in this first step toward a lymphoid cell fate. Once generated, CLP provide the cellular substrate for generation of adaptive B and T cells, via specific further specification and commitment to the B- or T-cell lineages. This process is critically controlled by a series of TF that initiate and reinforce the B- or T-cell programs, while again dominantly repressing alternative lymphoid options (reviewed in 5). Within the B-cell pathway, this involves coordinated expression of E2A, FoxO1, and Runx proteins that coordinate with IL-7 signals to induce de novo expression of Ebf1 and Pax5. The latter are critical for establishing the B-lineage program through transcriptional activation of B-cell-specific genes, such as Cd19 and Cd79a (Iga) (7, 8). In contrast, the T-cell pathway is initiated within the thymus microenvironment when the essential Notch1 receptor is triggered by the Delta-like ligand 4 expressed on thymic epithelial cells (9, 10). Activation of the Notch1 pathway in thymus settling progenitors (essentially a subset of CLPs with thymus-homing potential) unleashes a feed-forward and repressive system distinct from the one that operates in B cells (reviewed in 5). This T-cell specification and commitment process involves a distinct set of essential TFs, including Tcf1, Bcl11b, and Gata3 (11–16). Components of the antigen receptor rearrangement machinery represent common molecular targets that must be activated in both the T- and B-cell programs. This process involves the Rag 1 and Rag2, as well as enzymes involved in DNA resealing (including terminal deoxynucleotidyl transferase, DNA-PK, Ku70, Ku80, and DNA ligase IV) all of which are upregulated in committed B- and T-cell precursors. Central to the process of antigen receptors is a concomitant exit from the cell cycle; this is necessary as DNA rearrangement during active replication can generate


DNA double-strand breaks that cause genomic instability leading to lymphocyte transformation (17). To safeguard against this, early B- and T-cell progenitors express high levels of E-proteins (including E12, E47, and HEB) that serve to shut down proliferation of early lymphoid progenitors while activating the immunoglobulin and T-cell receptor loci that are engaged to create antigen receptors (18). Lymphocyte signatures that define and maintain B- and T-cell identity Following their generation in primary lymphoid organs, mature B and T cells enter the bloodstream where they circulate through lymphoid tissues. Antigen activation generates a second wave of cellular differentiation that creates specialized T-helper (Th) cell subsets with a new set of functions, while follicular helper T cells promote and coordinate the germinal center response that creates and then selects high affinity antibody responses (19, 20). Despite this complex process of adaptive lymphocyte diversification, B cells and T cells retain a selective transcriptional ‘core’ signature that defines their ‘identity’. This naturally includes the clonotypic B- and T-cell antigen receptors and their associated signal transduction modules, but also a small set of mRNAs that include differentiation antigens and TF [i.e. Cd19 and Pax5 for B cells versus Cd3e and Bcl11b for TCRab T cells (21)]. Beyond this ‘central’ B- and T-cell identity, there are several TF programs that characterize Th cell subsets (Th1-Tbx21, Th2-Gata3, Th17-Rorc, Treg-Foxp3, etc.) and B-cells subsets (memory B cells-Bcl6, plasma cells-Prdm1) that are epigenetically regulated and are essential for maintenance of specialized lymphocyte effector functions (22). The question therefore arises as to whether persistent expression of these different TF is required for maintenance of these transcriptional signatures that define lymphocyte ‘identity’? While a complete answer to this question is not yet available, there are reports that persistent expression of ‘master’ TF is required to maintain B- and T-cell identity. B-lineage commitment at the pro-B cell stage involves the TF Pax5 and in its absence, early B-cell precursors retain the capacity to pursue alternative hematopoietic cell fates, including both lymphoid (T, NK) as well as non-lymphoid (DC, macrophage, granulocyte, osteoclast) (23–25). More surprisingly, conditional ablation of Pax5 in fully mature B cells also results in the loss of B-cell transcriptional identity with a decrease in the expression of Cd19, Cd72, Cd79a, and Blnk and derepression of myeloid genes such as Csf1r (7). In an analogous fashion, the TF Bcl11b that is critical for T-cell commitment in early thymocyte progenitors (13–15) has been proposed © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Immunological Reviews 261/2014

Di Santo  Transcriptional signatures and ILC identity

to maintain T-cell identity as its conditional deletion in mature thymocytes and peripheral CD4+ T cells results in a loss of several T-cell-specific transcripts and a conversion into natural killer-like cells that express a cytolytic program (15). As such, both Pax5 and Bcl11b are proposed to functionally maintain mature B- and T-cell identity through transcriptional activation of ‘signatures’ and repression of alternative cell fates. These observations raise a question in relation to other lymphocyte lineages. Is persistence of particular TF expression a requisite for maintaining identity (signatures) of innate lymphocytes? Is TF modulation a relevant mechanism to regulate innate lymphoid cell homeostasis and function? Innate lymphoid cells: innate equivalents of differentiated T cells ILCs are a diverse family of innate immune effectors. Strikingly, ILCs have many functional characteristics of differentiated Th cells and, as such, can be thought of as innate versions of these adaptive T cells. Three groups of ILCs have been defined based on functional capacities and phenotypic markers (reviewed in 26, 27). Group 1 ILC (or ILC1) comprise NK cells (conventional and tissue-resident) and other interferon-c-producing innate lymphocytes characterized by expression of the transcription factor T-bet (1, 28–31). ILC1 have been shown to play a major role in the defense against viruses, intracellular bacteria, and some parasites. Group 2 ILC (or ILC2) secrete large amounts of type 2 cytokines (including IL-5 and -13) under the control of the transcription factors GATA-3 and the nuclear hormone receptor retinoic acid related orphan receptor a (RORa) (32–35). ILC2 are important in the immune response against helminth infections and are also associated with conditions characterized by airway inflammation (including allergic asthma) (reviewed in 36). Group 3 (or ILC3) includes several phenotypically distinct cells that express and require the transcription factor RORc to produce the Th17-associated cytokines IL-17 and IL-22 (37–40). ILC3 include lymphoid tissue inducer cells (LTi) that orchestrate lymphoid organ formation during embryogenesis and persist into adulthood (reviewed in 41). ILC3 are enriched at mucosal sites and appear to regulate barrier function and epithelial cell homeostasis via a unique hematopoietic ⟷ non-hematopoietic cell ‘cross-talk’ (reviewed in 42). ILCs represent a novel branch of hematopoietic tree that emerges under the control of specific TFs. Under steadystate conditions, ILCs have morphological characteristics of lymphoid cells (uniform nucleus, scant cytoplasm) and are © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Immunological Reviews 261/2014

developmentally derived from lymphoid precursors, including CLP (1, 2, 33, 43). As such, ILCs are clearly lymphoid in nature. While ILCs express many of the same TFs, surface markers and effector molecules that are characteristically expressed by their adaptive counterparts, ILCs can be clearly distinguished from T and B cells by their lack of clonotypic antigen receptors and by their independence from the DNA rearrangement machinery (1, 33, 37, 40). Moreover, many ILCs can develop in a thymus-independent fashion. Finally, ILCs are early effectors of immunity, responding within minutes/hours after activation, whereas adaptive immunity normally requires days/weeks to fully differentiate from na€ıve precursors. As such, ILCs provide a means to rapidly respond to infection or inflammation and thereby complement the adaptive arm of the immune system that can provide specific and long-term memory. ILC development stage I: Id2 leads the way In one well-supported model of lymphopoiesis, each of the three major lymphocyte subsets (B, T, and ILC) derives from the same CLP (2). The pathways of B- and T-cell development are well characterized (reviewed in 5) and several critical TFs that drive the early specification and commitment of B- and T-lineage precursors from CLP have been identified (Fig. 1). In contrast, the TF that control the emergence of ILC from CLP remain largely unknown. One protein that appears to critically orchestrate ILC development is the transcriptional repressor Id2. Id (inhibitor of DNA binding) proteins comprise a family of four members (Id1-4) that harbor bHLH domains but lack DNA-binding activity (reviewed in 44). Id proteins function as transcriptional repressors by heterodimerizing and sequestering bHLH-containing DNA-binding TFs [including the ‘E’ proteins E2A (that comprises E12 and E47), E2-2 and HEB]. Id proteins therefore titrate E-protein transcriptional activity within the cell. Genetic ablation of Id2 has many effects in the hematopoietic system, but notably causes a selective block in lymphocyte development. Interestingly, adaptive B- and T-cell development is permissive in the absence of Id2, whereas all ILC development is abrogated (33, 45, 46). This selective Id2 effect on ILC suggests a determinant role for E-protein activity in dictating development of lymphoid precursors for adaptive versus innate cells. As mentioned above, E-protein activity is critical for generation of early B- and T-lineage cells as perturbations in E2A, E2-2, and HEB strongly affect early B- and T-cell development (47–51). These observations suggest a model whereby induction of Id2 in


Di Santo  Transcriptional signatures and ILC identity

Fig. 1. A model for innate lymphoid cell (ILC) development from committed lymphocyte precursors. Stages of ILC development include those comprising ‘common’ ILC precursors (ILCp; stage I), ‘helper’ (ChILP) versus ‘killer’ (NKP) (stage II), ILC diversification (stage III), and mature ILC stability/plasticity (stage IV). ChILP, common helper ILC precursors; CLP, common lymphoid progenitors; HSC, hematopoietic stem cell; PLZF, promyelocytic leukemia zinc finger; NKP, NK precursors. For further details, please see the text.

lymphoid precursors would act to inhibit E-protein-mediated B- and T-cell development, while allowing CLP to differentiate along the ILC fate. Absence of Id2 abrogates ILC development as lymphoid precursors can only follow the Band T-cell pathway. In accordance with this model, overexpression of Id proteins in early lymphoid precursors can inhibit B- and T-cell development (52, 53), while strongly promoting development of NK cells that belong to the ILC pathway. Thus, ILC development begins with a first stage that segregates ILCs from adaptive B and T cells via modulation of E-protein activity in lymphoid precursors. The proposed model of lymphopoiesis makes several predictions regarding the nature of the first committed ILC precursors (ILCp). ILCp should have lymphoid potential, lack B- and T-cell potential, possess ILC potential (generate all yet identified ILC groups at the single cell level), and should express Id2. Do such ‘common’ ILCp exist? For the moment, the answer is no, although related ILC precursors (see below) come close. The identification of a common ILCp would provide a means to define the transcriptional signature for cells within the ILC branch of the hematopoietic tree. A central question for determining lymphoid fate concerns the balance between Id2 and E-protein expression in


lymphoid precursors. CLPs express little if any Id2 and therefore induction of Id2 expression would initiate the emergence of ILC from lymphoid precursors. The inductive signals for Id2 expression in CLP are not clearly identified but likely involve extrinsic factors that are present in the bone marrow microenvironment. Bone morphogenic proteins that trigger the Smad pathway may be involved (54). In contrast, as upregulation of E-protein expression drives B- and T-cell development, its absence could likewise favor ILC generation from CLP. This particular situation (absence of E-proteins) is permissive for ILC development (at least for NK cells) even in the absence of Id2 (55), further demonstrating the important role for E-proteins in promoting B- and T-cell generation from CLP at the expense of ILCs. Thus, it is the balance of E-protein/Id2 activity in CLP that determines ILC precursor fate. ILC development stage II: segregation of ‘helper’ and ‘killer’ ILC precursors The critical role for Id2 in regulating ILC fate prompted the search for Id2-expressing committed ILC precursors. Recently, two reports described such precursors that were present in murine fetal liver and adult bone marrow (1, 56). One group utilized Id2-GFP reporter mice (57) to characterize a rare line© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Immunological Reviews 261/2014

Di Santo  Transcriptional signatures and ILC identity

age-negative, IL-7Ra+ BM subset that co-expressed a4b7 integrins. This particular cell surface marker was chosen as previous studies identified that expression of a4b7 was associated with an unusual lymphoid precursor population that had lost B- and T-cell potential, but retained capacity to generate NK cells, dendritic cells, and LTi cells (58, 59). Within the a4b7+ IL-7Ra+ population, an Id2+ population was discovered that had properties of a committed ILC precursor. This subset (denoted ChILP for common helper ILC precursor) was able to generate a subset of ILC1, ILC2, and both NKp46+ and CD4+ ILC3 (LTi cells) after in vivo transfer into immunodeficient mice (1). Moreover, single ChILP could generate multiple ILC subsets in vitro after culture on OP9 stromal cells that expressed DLL4. Interestingly, ChILP could not give rise to conventional NK cells in vivo or in vitro. As such, this group proposes that ChILP are committed ILC precursors for all ‘helper’ ILC subsets and not for ‘killer’ ILCs (that include NK cells) (1). A second group created CreGFP reporter mice by modifying the locus of the TF encoding the promyelocytic leukemia zinc finger (PLZF) (encoded at Zbtb16). This approach allows for identification and lineage-tracing (fate-mapping) of PLZF-expressing cells. During the characterization of PLZFCreGFP mice, this group observed an interesting minor BM subset that expressed GFP and was lineage-negative, IL-7Ra+, and a4b7+ (56). These PLZF+ lymphoid precursors could give rise to multiple ILC subsets (but not T, B, or myeloid cells) after in vivo transfer and were also able to generate ILC1, ILC2, and ILC3 in vitro at the single cell level (56). Interestingly, PLZF+ cells had poor NK cell reconstituting ability and did not generate CD4+ ILC3 (LTi cells) in vivo or in vitro. Thus, these PLZF+ a4b7+ cells, like ChILP, appeared to represent committed ILC precursors, especially for ‘helper’-like ILC subsets. The PLZF+ cells were clearly related to ChILP: PLZF+ cells expressed high levels of Id2 and a large fraction of ChILP expressed PLZF (1, 56). Moreover, PLZF expression could be induced in PLZF a4b7+ precursors following exposure to Notch ligands suggesting that a precursor–product relationship existed between these two populations. Taken together, these two reports identify committed ILC precursors for ‘helper’ ILC subsets but also suggest that these precursors are heterogeneous. The identification of ChILP and PLZF+ ILC precursors represent important steps toward an understanding of the molecular mechanisms that regulate the emergence of ILC precursors from multi-potent lymphoid progenitors. The relative absence of NK cell potential from PLZF+ ILCp and ChILP suggests the existence of additional precursors dedicated to the NK cell lineage. Previous studies have © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Immunological Reviews 261/2014

identified the earliest committed NK cell progenitors (NKP) in the adult bone marrow that could give rise uniquely to NK cells but not B, T or myeloid cells (60–62). Whether these phenotypically defined NKP have potential to generate other ILC is not known. In one study (60), these NKP clearly expressed Id2, although the relationship of NKP with Id2expressing ChILP remains unclear. If these NKP represent truly NK committed progenitors (restricted to the NK lineage), this would strongly support a model of ILC development with segregation of ‘helper’ ILCp and ‘killer’ ILCp that derive from a ‘common’ ILCp (Fig. 1). ILC development stage III: functional diversification of ‘helper’ ILC subsets A third stage of ILC development involves the functional diversification of the different ILC groups (ILC1, ILC2, ILC3) from ILC precursors (Fig. 1). By analogy with Th cell differentiation from naive T cells, this process would involve upregulation of the TF that help to distinguish these ILC groups, including Tbx21 (T-bet) for ILC1, Gata3 and Rora for ILC2, and Rorc (encoding RORct) for ILC3 (reviewed in 27). How these distinct TF are selectively induced in different ILC groups remains a mystery. During Th differentiation, soluble factors (cytokines) elaborated by DCs and other antigen-presenting cells collaborate with TCR triggering in the context of costimulatory molecules. ILC lack antigen receptors but retain their critical downstream signaling cascades (ITAM-associated tyrosine kinases ZAP-70 and Syk). As such, ITAM pathways may be involved in some ILC diversification, although not for NK cells (63). Mature ILC express a plethora of cytokine receptors (for IL-1, -2, -6, -7, -9, -12, -15, -23, -25, -33, among others), their downstream JAK/STAT and Myd88 pathways and several costimulatory molecules that may be involved in the differentiation of distinct ILC subsets. While some cytokine receptors appear redundant for generation of certain ILC subsets (IL-12R for ILC1, IL-33R for ILC2, IL-23R for ILC3), a complete analysis is not yet available. In addition, it is not known which of these receptors are expressed by committed ILC precursors (that provide the substrate for further ILC differentiation) and can therefore trigger an ILC diversifying signal. One possibility is that environmental signals (cytokines? cell-associated ligands? microbial products? dietary factors?) differ depending on the type of invading infectious pathogen and the age of the host, and these signals then drive development of the most appropriate ILC group to address the situation at hand. This scenario would require that


Di Santo  Transcriptional signatures and ILC identity

ample ILC precursors be available within the organism that could then respond in the case of inflammation or infection. An alternative notion is that the TF profiles that characterize diverse ILC subsets are not induced from ILCp but are rather ‘hardwired’ (intrinsically programmed) during development to create different ILC subsets that are then recruited and potentially amplified depending on the immune context. Unfortunately, there is little data currently available to distinguish between models for ‘induced’ versus ‘hardwired’ diversification of ILC subsets from committed ILC precursors. ILC development stage IV: stability versus plasticity of ILC functions A final stage of ILC development concerns the stability of effector functions within the mature ILC compartment. Initially, Th subsets were proposed to have stable effector phenotypes, although more recent data have challenged this notion and rather suggest that Th cells may exhibit functional plasticity depending on the environmental context (19). Epigenetic modifications appear to play a central role in determining Th cell stability versus plasticity (22) through regulation of key TFs that are associated with cytokine secretion and other functional profiles. Nevertheless, persistent TF expression is required for maintenance of certain effector functions in Th cells (e.g. Gata3 required for type 2 cytokine secretion in Th2 cells, Foxp3 for Treg function) (64, 65). As ILC are generally considered as innate equivalents of CD4+ Th cells and CD8+ CTLs, one may ask whether similar rules apply to the stability and plasticity of ILC effector functions. This type of analysis can be extended to consider the definition and potential mechanisms that maintain ILC ‘identity’. During the initial stages of ILC development, several transcription factors have been identified that are critical for generation of the earliest ILC precursors (Id2) or block the earliest stages of a particular ILC subset (Nfil3 for NK cells) (66–68). The mechanism by which Id2 controls ILC emergence has been considered above and recent study suggests that Nfil3 may in part regulate early NK cell generation via Id2 (68). As such, persistent Id2 expression in ILC and Nfil3 expression in NK cells may represent part of a molecular signature that helps to define the ‘identity’ of these cells. It is not known whether continuous Id2 expression is required for maintenance of ILC homeostasis or function. In contrast, recent studies demonstrated that conditional deletion of an Nfil3flox allele in developing NKp46+ cells (69) had little


impact on overall homeostasis of mature NK cells and did not affect the capacity of NK cells to proliferate and differentiate following MCMV infection. These observations suggest that Nfil3 plays a critical context-dependent role during the emergence of NK cell precursors from CLP but has a redundant role in mature NK cells. As such, Nfil3 function in the NK lineage differs from that of Pax5 in B cells and Bcl11b in T cells. Is there any evidence for a requirement of persistent TF expression in the maintenance of ILC functions? Previous studies in Th subsets demonstrated that modulation of ‘master’ TF influenced the functional output of fully differentiated CD4+ T cells (reviewed in 70). Examples include the requirement for persistent Gata3 expression for Th2 function and Foxp3 expression for Treg suppressive activity (64, 65). Concerning maintenance of effector functions in ILCs, two studies documented an important functional role for persistent Gata3 expression in mature ILC2 to maintain Th2 cytokine production capacity and cytokine receptor expression (71, 72). In contrast, in ILC3 (that express Gata3 throughout their lifetime) constitutive ablation in lymphoid progenitors but not conditional deletion in mature cells affected generation and peripheral homeostasis (71, 73). Finally, two reports proposed that modulation of TF expression in differentiated ILC subsets could alter the functional capacity of these innate effectors (30, 74). Both reports involved the study of ILC that differentially expressed the TF Tbx21 and Rorc and suggested that transitions between T-bet+ ILC1 and Rorgt+ ILC3 could occur depending on the environmental context. On the surface, this situation resembles an innate version of Th1-Th17 plasticity that has been previously proposed to occur during inflammation (reviewed in 75) and may be regulated by similar mechanisms. Concluding remarks The transcriptional control of innate lymphocyte development shares many parallels with its adaptive counterparts. The current model provides a conceptual framework for identifying and isolating critical developmental intermediates that will allow a continuous roadmap from lymphoid committed progenitors to mature functional ILCs. Many questions remain as to the mechanisms by which critical TF control this process; advances in epigenetic techniques that allow analysis of small numbers of cells will hopefully allow the transcriptional circuits of ILC differentiation to be described in the same detail as for T and B cells. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Immunological Reviews 261/2014

Di Santo  Transcriptional signatures and ILC identity

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Staying innate: transcription factor maintenance of innate lymphoid cell identity.

Innate and adaptive lymphocytes are characterized by phenotypic and functional characteristics that result from genomic rearrangements (in the case of...
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