A Defining Factor For Natural Killer Cell Development

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particular subunits of RNA polymerase III whether RNA isolated from the nucleus of 1. Takeuchi, O. & Akira, S. Immunol. Rev. 227, 75–86
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A defining factor for natural killer cell development


© 2009 Nature America, Inc. All rights reserved.

James P Di Santo
Transcription factors are critical regulators of cell fate in the hemato-lymphoid system. New evidence indicates
that the basic leucine zipper transcription factor E4BP4 (also known as NFIL3) is essential for natural killer cell
specification.

L ymphocyte development from


hematopoietic stem cells is a carefully
orchestrated process that integrates signals
NKP
E4BP4
Id2
NK
O K
CD4+ T

Th-P
(both cell-associated, membrane-bound Notch1 PLZF
factors and soluble factors) elaborated by HSC ELP TSP pro-T NKT
GATA-3 SO
stromal cells in the bone marrow and thy- X1
3
mic microenvironments. These extrinsic EBF
Nonlymphoid pro-B B γδ T
signals converge in the nuclei of respond- Pax5
lineages
ing hematopoietic precursors and regulate
a multitude of transcriptional targets nec-
essary to guide the cells along distinct dif- Figure 1 Transcription factor control of lymphoid lineage development. The key transcription
ferentiation pathways leading to lymphoid factors E4BP4, Id2, Notch, GATA-3, EBF, Pax5, Th-POK, PLZF and SOX13 have been identified as
precursors and later to fully differentiated being essential for the development of various lymphoid cell types. HSC, hematopoietic stem cell;
B cells, T cells or natural killer (NK) cells. ELP, early lymphoid precursor; TSP, thymus-settling cell; pro-B, pro–B cell; pro-T, pro–T cell;
B, B cell; T, T cell.
Central to this process are a variety of tran-
scription factors that have the ability to
form higher-ordered, multiprotein com- opment has remained elusive, and it has (and perhaps other lymphocytes with innate
plexes that interact with DNA and modify remained possible that NK cell development characteristics).
the transcriptional activity of particular represents a ‘default pathway’ used when E4BP4 was initially identified by its abil-
target genes. ‘Master’ transcription factors other lymphoid lineages are not directly ity to repress viral transcription and to
essential for the development of B cells and specified. In this issue of Nature Immunology, promote IL-3-dependent survival of pro–B
T cells (including αβ T cells, γδ T cells and Brady and colleagues put this issue to rest cells2. Subsequent molecular characteriza-
NKT cells) have been identified, which has by identifying E4BP4 (E4-binding protein 4; tion has demonstrated that E4BP4 contains
provided key information about how these also known as NFIL3 (nuclear factor inter- a canonical bZIP motif, which places this
lymphoid subsets are generated (Fig. 1). In leukin 3 (IL-3) regulated)), a basic leucine transcription factor in the extended bZIP
contrast, a defining factor for NK cell devel- zipper (bZIP) transcriptional activator, as protein family that includes several hun-
a critical transcription factor required for dred members in different species, includ-
NK cell development 1. These landmark ing CREB, ATF, AP1 and C/EBP proteins;
James P. Di Santo is in the Cytokines and Lymphoid observations provide a framework for fur- E4BP4 belongs to the proline- and acid-
Development Unit, Institut Pasteur, and Institut ther delineation of the processes involved in rich subfamily2. The bZIP proteins are
National de la Santé et de la Recherche Médicale NK cell lineage commitment and indicate critically involved in the control of diverse
U668, Paris, France. involvement of this bZIP-family transcrip- developmental processes in and outside the
e-mail: disanto@pasteur.fr tion factor in the differentiation of NK cells hematopoietic system, which suggests E4BP4

nature immunology volume 10 number 10 october 2009 1051


ne w s and v ie w s

might serve a role during hemato-lymphoid mainly by promoting NK lineage commit- by other transcription factors that can com-
development. Although E4BP4-deficient ment. Although the authors do not formally pensate for E4BP4.
mice (Nfil3–/–; called ‘E4bp4–/–’ here) develop address this hypothesis, the fact that E4BP4 The notion that E4BP4 may be redundant
without apparent abnormalities and have is required at the earliest stage of NK cell for the activation of certain transcriptional
an essentially normal hematopoietic and development (E4bp4–/– mice have normal targets in some cell types may also explain
lymphoid profile, mature NK cells (identi- numbers of NKPs but considerably fewer the lack of any obviously altered phenotype
fied as CD3–NKp46+NK1.1+) are conspicu- immature and mature NK cells) is consistent of NKT cells and memory CD8+ T cells in
ously absent from the bone marrow, spleen with a role for E4BP4 in the specification of E4bp4–/– mice. Like NK cells, these cell types
and blood. Furthermore, classical NK cell NK cells. As NKPs comprise a heterogeneous show constitutive E4BP4 expression that can
functions (such as elimination of major his- population (only 10% give rise to NK cells be enhanced by IL-15, but their homeostasis
tocompatibility complex class I–deficient in vitro5), E4BP4 expression may provide a is unaffected by the absence of E4BP4 (ref. 1).
target cells and production of interferon-γ) more precise marker for the identification of One explanation for this difference in sensitiv-
are not detected in E4bp4–/– mice, whereas true NKPs as well as the extracellular triggers ity might involve enhanced responsiveness of
influenza-specific antiviral CD8 + T cell that lead to their specification. these T cell subsets to related growth factors.
responses are intact, which suggests a severe What are the molecular targets of E4BP4 In this context, another common γ-chain–
and selective NK cell deficiency. Using irra- transcriptional activation? Here, Brady and dependent cytokine (IL-7) has been shown
diated bone marrow chimeras, Gascoyne colleagues analyze E4BP4-sufficient and to compensate for IL-15 in memory T cell
et al. show that hematopoietic expression of E4BP4-deficient hematopoietic precursors homeostasis11. Still, a more complete analy-
E4BP4 is required for normal NK cell devel- and show that expression of the basic helix- sis of NKT and memory CD8+ T cell function
© 2009 Nature America, Inc. All rights reserved.

opment1; this is important, as E4BP4 expres- loop-helix inhibitor Id2 is much lower in in E4bp4–/– mice is warranted before the pos-
sion outside the hematopoietic system2 could the absence of E4BP4. Id2 has been shown sibility of a role for E4BP4 in the maturation
have conditioned a lymphopoietic microen- to serve a critical role in NK cell homeosta- of these cells is excluded. In a similar fashion,
vironmental niche critical for NK cell gen- sis (Id2–/– mice have much lower NK cell although studies of E4bp4–/– mice have identi-
eration. They also find that ectopic retroviral numbers than wild-type mice6) by oppos- fied a critical role for E4BP4 during early NK
expression of E4BP4 in hematopoietic stem ing the activity of E-box transcription fac- cell development, conditional ablation studies
cells promotes NK cell development in vitro tors, which strongly promote B cell and T cell will be needed to address whether persistent
and partially corrects the NK cell deficiency lymphopoiesis7. Gascoyne et al. show that E4BP4 expression is required for maintenance
of E4bp4–/– mice in vivo1. Collectively, these E4BP4 induces Id2 expression and that ecto- of NK cell function.
studies identify E4BP4 as the first transcrip- pic Id2 expression partially restores NK cell Finally, E4bp4–/– mice may provide a new
tion factor known to be selectively and criti- development in vitro from E4BP4-deficient tool for studying diurnal regulation in the
cally required for NK cell development. hematopoietic precursors1. These data are immune system. Published studies of droso-
As previous studies have indicated involve- consistent with a transcription factor cascade phila and chickens have suggested a role for
ment of E4BP4 in growth factor–dependent in which E4BP4 induces Id2 expression in E4BP4 homologs in the regulation of cir-
lymphocyte survival, Gascoyne et al. go on early lymphoid precursors, which can then cadian ‘clocks’2. These ‘clocks’ are activity
to investigate a possible link between E4BP4 promote the NK cell fate8. rhythms that oscillate intrinsically but are
and soluble factors known to be involved in Id2 has critical developmental roles beyond synchronized by environmental cues and are
NK cell development. ‘Trans-presentation’ of its ability to promote NK cell development9. In controlled by autoregulatory transcription
IL-15 by membrane-bound IL-15 receptor-α the hematopoietic system, Id2 has an essential and translation feedback loops 12. Diurnal
represents the essential ‘fuel’ that drives the role in the differentiation of dendritic cells, regulation of innate and adaptive immune
differentiation of immature NK cells (iNK osteoclasts and lymphoid tissue-inducer cells, function is an emerging field 13, and the
cells) from committed NK cell precursors a population of CD3–CD4+CD117+CD127+ identification of E4BP4 expression in innate
(NKPs) and maintains the homeostasis of cells that constitutively express the gene lymphocytes could provide a means of sub-
mature peripheral NK cells3. E4BP4 expres- encoding the transcription factor RORγt and stantiating molecular ‘clock’ mechanisms in
sion is detected in NKPs, is upregulated in are required for the development of prepro- these cells of the innate immune response.
immature NK cells and is maintained in grammed and induced lymphoid structures,
mature NK cells. This expression pattern including Peyer’s patches, lymph nodes and 1. Gascoyne, D.M. et. al, Nat. Immunol. 10, 1118–1124
(2009)
correlates with the IL-15 dependency of intestinal cryptopatches10. Given a model 2. Cowell, I.G. Bioessays 24, 1023–1029 (2002).
these different stages of NK cell develop- in which E4BP4 controls Id2 expression, it 3. Di Santo, J.P. Annu. Rev. Immunol. 24, 257–286
(2006).
ment4 and suggests a model in which E4BP4 would be expected that the phenotypes of 4. Vosshenrich, C.A. et al. J. Immunol. 174, 1213–1221
is a critical transcriptional target that medi- E4bp4–/– mice and Id2–/– mice would con- (2005).
ates the biological effects of IL-15. In sup- verge. However, this does not seem to be the 5. Rosmaraki, E.E. et al. Eur. J. Immunol. 31, 1900–1909
(2001).
port of this view, Gascoyne et al. show that case, as E4bp4–/– mice have normal develop- 6. Boos, M.D., Yokota, Y., Eberl, G. & Kee, B.L. J. Exp.
IL-15 enhances E4BP4 expression in IL-15- ment of lymph nodes and Peyer’s patches Med. 204, 1119–1130 (2007).
responsive target cells and that ectopic (H. Brady, personal communication), which 7. Yokota, Y. et al. Nature 397, 702–706 (1999).
8. Fujimoto, S., Ikawa, T., Kina, T. & Yokota, Y. Int.
expression of E4BP4 allows some degree of suggests that lymphoid tissue–inducer activ- Immunol. 19, 1175–1182 (2007).
NK cell development from hematopoietic ity is largely intact in the absence of E4BP4. 9. Yokota, Y. Oncogene 20, 8290–8298 (2001).
10. Eberl, G. Trends Immunol. 28, 423–428 (2007).
stem cells when IL-15 signaling is blocked1. Nevertheless, these observations point to a 11. Kieper, W.C. et al. J. Exp. Med. 195, 1533–1539
Interestingly, the positive effects of E4BP4 on cell type–specific control of Id2 expression (2002).
NK cell homeostasis do not seem to involve in the hematopoietic system that may be 12. Hastings, M., O’Neill, J.S. & Maywood, E.S.
J. Endocrinol. 195, 187–198 (2007).
improved survival or proliferation, leading achieved through transcriptional activation 13. Arjona, A. & Sarkar, D.K. Neurochem. Res. 33, 708–
Gascoyne et al. to propose that E4BP4 acts by alternative members of the bZIP family or 718 (2008).

1052 volume 10 number 10 october 2009 nature immunology

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