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Seminars in Immunology 23 (2011) 315– 316

Contents lists available at SciVerse ScienceDirect

Seminars in Immunology

jo u rn al hom epage: www.elsev ier .com/ locate /ysmim

ntroductory perspective

The developmental analysis of various lineages of the innatend adaptive immune system has benefited from an experi-ental framework that was initially established for analyzing

ematopoiesis. A dominant methodological approach has involvedhe isolation of discrete intermediates from the bone marrow orhymus and the prospective analysis of their developmental poten-ials upon transplantation in vivo and/or differentiation in vitro.uch analyses along with lineage tracing studies that are not depen-ent on removal of developmental intermediates from their cellulariches have refined as well as clarified various developmental rela-ionships. In the past decade tremendous progress has been made inlucidating components of gene regulatory networks that orches-rate the development of distinct lineages of the immune systemnd its numerous effector cells. The components of these net-orks comprise transcription factors, microRNAs and chromatinodifying complexes as well as signaling systems that induce or

ntagonize the expression and/or activity of the gene regulatorypparatus. By connecting transcription factors to their target genes,articularly using genome-wide chromatin crosslinking and immu-oprecipitation (ChIPseq), it has now become possible to rapidlyssemble complex gene regulatory networks that control cell fatepecification and commitment. These networks in turn reveal theolecular interplay of specific combinations of transcription fac-

ors in turning on lineage appropriate genes and in shutting downlternate lineage genes that had been primed for activation. Fur-hermore the networks are seen to comprise of feed back and feedorward regulatory loops that enable discrete cell fate choices orevelopmental transitions within a lineage.

The current volume of Seminars in Immunology contains contri-utions from leading laboratories in developmental and molecular

mmunology that have fueled rapid progress in this area. It opensith a pair of articles from the Murre and Sieweke labs that

ocus on the development of the immune system in the con-ext of hematopoiesis. Murre not only details the advances maden the analysis of new developmental intermediates, particularlyhe lymphoid-primed multipotent progenitor (LMPP), and theefinement of lineage relationships but also the complex set ofranscriptions factors that control the generation of the variousell types. The use of ChIPseq to identify sets of target genes thatre bound and regulated by these transcription factors and alsoo monitor chromatin modifications that precede or follow DNAinding interactions represents a major advance. Murre describestudies that have been conducted in the context of B cell devel-

pment and their mechanistic implications for the developmentalontrol of gene activity. Sieweke focuses on a complementary issuen hematopoiesis and developmental immunology namely whether

044-5323/$ – see front matter © 2011 Elsevier Ltd. All rights reserved.oi:10.1016/j.smim.2011.10.003

cell fate choice is based on stochastic versus instructive mecha-nisms. Although there is considerable evidence to suggest that Band T cell development requires instructive inputs from the IL-7receptor and Notch signaling systems respectively, there has beenconsiderable controversy around the roles of various hematopieticcytokines in the generation of erythroid and myeloid lineages, thelatter encompassing innate immune cells. Sieweke reviews the ear-lier literature and recent studies involving single cell analysis andthe imaging of cell fate choice. The new findings reinforce a keyrole for hematopoietic cytokines such as M-CSF in providing aninstructive input to the gene regulatory apparatus in controllingcell fate specification. M-CSF by regulating the expression of thetranscription factor PU.1 in a context specific manner promotesdevelopment of myeloid lineages and antagonizes erythropoiesis.Furthermore PU.1 induces M-CSF receptor expression thereby rein-forcing myeloid cell fate choice through a positive feed back loop.

The B and T lineages have long served as leading exemplarsfor analyzing developmental and molecular mechanisms that reg-ulate cell fate choice and commitment. Sigvardsson and Nutt focuson the early and late developmental events, respectively in the Blineage. Sigvardsson details the molecular circuitry that leads tothe specification of the B cell fate and the closing down of alter-nate developmental potentials including myeloid, NK and T cellfates. Nutt reviews the advances that have been achieved in elu-cidating a gene regulatory network that controls B cell activation,immunoglobulin class switch recombination and somatic hyper-mutation and plasma cell differentiation. This network involvesmutually antagonistic transcription factors that regulate the ger-minal center versus plasma cell fates. Switching between differentstates of the network appears to involve differing concentrationsof pivotal transcription factors, IRF-4 and Blimp-1, whose expres-sion is regulated by extrinsic signals and which mutually regulateeach other’s expression to reinforce the plasma cell fate. Zuniga-Pflucker, Bosselut and Moroy cover recent molecular advances inthe analysis of T cell development spanning cell fate specification,the CD4 versus CD8 T lineage options and the generation of distincttypes of effector cells in the periphery. Early T cell developmenthas achieved major advances through molecular insights into therole of Notch signaling in T cell fate specification and the recentdemonstrations of the critical functions of the transcription factorsTCF-1 and Bcl11b. These latter two regulatory proteins appear torepresent the T-lineage counterparts of the B lineage determiningtranscription factors EBF-1 and Pax5. Bosselut focuses on the CD4

versus CD8 T cell fate choice and the mutual antagonism betweenthe transcription factors Runx3 and ThPok in regulating this majordevelopmental decision in the thymus. The richly detailed analysis

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16 Introductory perspective / Semin

f the molecular mechanism by which the CD4 gene undergoesranscriptional silencing in the CD8 lineage serves as a power-ul model for elucidating epigenetic processes that underlie theevelopmental control of gene activity within the immune system.oroy details the numerous critical functions of the transcription

actor Gfi-1 in hematopoiesis in particular its requirement for theevelopment and functioning of T-lineage cells.

The volume ends with a chapter by Murphy and colleagues onhe molecular circuitry that controls the generation of various typesf dendritic cells. In spite of their fundamental import to the func-ioning of the immune system, molecular analysis of regulatoryroteins that orchestrate the development of dendritic cells has

agged behind those of other immune cells such as B and T lympho-ytes. However recent advances with insights into the roles of theranscription factors Id2, PU.1, Spi-B, IRF-4,8 and Batf have greatlyccelerated the delineation of the gene regulatory network that

Immunology 23 (2011) 315– 316

underpins dendritic cell development and this area is now poisedfor deeper analysis using the genomic tools such as ChIPseq thatare being deployed for the B and T lineages.

I wish to thank colleagues who have contributed their valuableinsights and syntheses of the rapidly expanding literature in thisarena. I am particularly indebted to Michael Julius for inspiring meto undertake the editing of a second volume focused on issues indevelopmental and molecular immunology based on his palpableexcitement about recent advances in the field.

Harinder SinghDepartment of Discovery Immunology, Genentech,

1 DNA Way, S. San Francisco, CA, USAE-mail addresses: singh.harinder@gene.com,

harindsi@gene.com