Over the past two decades, astrophysi-cists have been spectacularly suc-cessful in explaining the early

evolution of the Universe. Existing theoriescan account well for the time span from theBig Bang nearly 14 billion years ago untilthe Universe began to cool and form thefirst large structures less than a millionyears later. But detailed explanations of howthe original stew of elementary particlessubsequently coalesced over time, to formthe stars and galaxies seen in the present-day Universe, are still being refined. As theyreport on pages 181 and 184 of this issue,Glazebrook et al.1 and Cimatti et al.2 havediscovered the most distant ‘old’ galaxiesyet. But the existence of these objects atsuch an early epoch in the history of theUniverse seems inconsistent with thefavoured theory of how galaxies formed.

That favoured theory is the so-calledhierarchical model, in which smaller struc-tures gradually accumulate into ever largerstructures,ultimately forming galaxies of thesort we see today3. The most massive galaxiesare expected to have formed relatively late inthe process,with few existing before the Uni-verse was half its present age. Such predic-tions can be tested, in principle, through theobservations made of distant galaxies.

Nature has provided us with a powerfulmeans of observing the history of the Uni-verse: because the speed of light is finite, aswe look out into space we actually peer backin time, seeing distant objects not as they arenow, but as they were when their light wasemitted millions or billions of years ago.Unfortunately, galaxies more than 6 billionlight years away are not only exceedinglyfaint, but are also particularly difficult toidentify. The visible galaxy spectra are ‘red-shifted’ to longer, near-infrared wavelengthsas a consequence of the expansion of theUniverse; at these wavelengths, the Earth’satmospheric emission obscures the key spectral ‘fingerprints’ that are commonlyused to identify galaxies.

For these reasons,virtually all of the galax-ies known from the early days of the Universeare those that are still forming new stars, andhence emitting copious amounts of light4.Although easier to find, such galaxies are not particularly useful for testing theories ofgalaxy formation because it is impossible toset strong lower limits on how old they are.However, finding significant numbers of

massive, evolved galaxies (which finishedforming stars long ago) at distances that cor-respond to half the present age of the Universewould indicate that such galaxies formedmuch earlier than the leading theory predicts.

Several earlier studies5–8 have found evi-dence for a population of evolved galaxies in the distant past. These studies used thecolours of galaxies as rough estimators oftheir distance — a method that is easier butalso much less accurate than measuringgalaxy distances directly through the redshiftof their spectrum. By pushing some of thelargest ground-based telescopes to their lim-its, Glazebrook et al.1 and Cimatti et al.2 havenow provided the most compelling evidenceyet that ‘old’ (that is, evolved) massive galax-ies were numerous at early epochs. Using the8-metre telescopes at the European SouthernObservatory in Chile to survey a small regionof the sky in detail, Cimatti et al.2 report the discovery of four massive, evolved galax-ies, all of which are considerably more distant than the previous record holder.Supplementary images from the HubbleSpace Telescope (Fig. 1) show that thesegalaxies appear to be massive and old, bothstructurally and spectroscopically.

Complementing this discovery is the ambitious Gemini ‘Deep Deep Survey’,which

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was performed using the Gemini observa-tory’s Hawaii-based 8-metre telescope. Thisstudy1 is notable both for the exceptionallylong exposures obtained (30 hours for eachtarget) and for the use of an innovativeobserving mode, which reduces backgroundnoise exceptionally well. As a result, Glaze-brook et al.1 were able to measure redshiftsfor far fainter galaxies than is possible byconventional means. As well as strengthen-ing the evidence that massive, evolved galax-ies were a significant component of theyoung Universe, the Gemini team has esti-mated the change in the abundance of suchobjects since that time, by observing addi-tional galaxies at intervening distances. They conclude that, going from the present dayback to the earliest epochs they probe, theabundance of massive galaxies decreasesmuch more slowly than predicted by thehierarchical model.

With this first solid confirmation1,2 thatas far back as 10 billion years ago there werealready many old massive galaxies, it is clearthat even the best models can’t fully explainthe evolution of galaxies. These studies areforcing astronomers to consider whethermassive galaxies grew much earlier than pre-dicted by the hierarchical model, or whetherthe stars in these earliest galaxies formed in a

Old before their timeGregory D. Wirth

The discovery of massive, evolved galaxies at much greater distances thanexpected — and hence at earlier times in the history of the Universe — is achallenge to our understanding of how galaxies form.

Figure 1 Journey to the early Universe. This image, taken in visible light by the Hubble SpaceTelescope, shows a plethora of galaxies billions of light years away in a random patch of sky called the Hubble Ultra Deep Field. As part of a survey of galaxies in this region, Cimatti et al.2 have foundseveral massive galaxies that were already fully assembled billions of years before they should havebeen, according to current theories. A complementary survey in the northern sky by Glazebrook et al.1

has revealed similar examples of such galaxies, posing a problem for theories of galaxy formation.

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substantially different way from our expec-tations9. As well as providing the motivationto explore new models of galaxy evolution,this is a tantalizing first look at the type ofscience that will become routinely possible asthe next generation of even larger telescopescome online in ten years’time. ■

Gregory D. Wirth is at the W. M. Keck Observatory,65–1120 Mamalahoa Highway, Kamuela,Hawaii 96743, USA.e-mail: wirth@keck.hawaii.edu

Immunology

Polarizing a T-cell response Sophie M. Lehar and Michael J. Bevan

Signals through Notch receptors regulate many developmentaldecisions. New evidence suggests that this pathway is also involved in dictating the tone of the immune response to infection.

We are plagued by pathogens rang-ing from small viruses to largemulticellular parasites, and have

evolved a corresponding array of protectiveimmune mechanisms mediated by different‘effector’ cells. To clear infections, theimmune system must first recognize thetype of pathogen involved and then mountan appropriate response. Papers in Cell1 andin Immunity 2 now show that the Notch signalling pathway, best known for its regulation of cell development, may alsodetermine the type of immune responsethat occurs.

In this case the effector cells are thymus-derived (T) lymphocytes that express anaccessory cell-surface molecule known asCD4. These CD4 T cells can become eitherTh1 or Th2 effector subsets, as defined bytheir ability to secrete unique combinationsof cytokine signalling molecules3. Th1 cellsmediate cellular immunity to viruses orintracellular bacteria by secreting gammainterferon (IFN-�); Th2 cells promote immunity to multicellular pathogens, suchas parasitic nematode worms,their signaturecytokine being interleukin-4 (IL-4).

T cells do not recognize pathogens directlybut rely on other cells — dendritic cells — asintermediaries4. Dendritic cells recognizepathogens through receptors that ‘see’ com-mon determinants found on pathogens. Thebest characterized of these receptors are theToll-like receptors5. After recognizing apathogen, dendritic cells migrate to the lymphoid organs, where they interact with T cells, transmitting information about thetype of infection encountered and inducinga T-cell response4. The upshot of this inter-action can dramatically affect the outcome of infection: inappropriate Th1 or Th2responses are associated with such seriousconditions as autoimmunity, allergy or theinability to clear infections3.

A Th1 response is initiated when dendriticcells are stimulated through their Toll-likereceptors; this induces the secretion of inter-leukin-12 (IL-12), which signals undifferen-tiated (naive) CD4 T cells to differentiateinto the Th1 lineage (Fig. 1). Th2 responsesare initiated when dendritic cells encountermulticellular parasites or allergens. But neither the receptors that recognize these‘type-2’ antigens nor the dendritic-cell-associated molecules that induce Th2responses are known.

The key cytokine involved in Th2 differ-entiation, IL-4, is produced by Th2 cells themselves. This is puzzling. If Th2 cells produce the cytokine required for their owndifferentiation, how is a Th2 response initi-ated? One possibility is that Th2 cells arise bydefault when a strong Th1 stimulus is lacking,but dendritic cells can induce Th2 responsesdirectly,even in the absence of IL-4 signals6.Soit has been proposed that dendritic cells inducedifferentiation of Th2 effectors through someas-yet uncharacterized pathway.

Amsen et al.1 and Tanigaki et al.2 provideevidence that the Notch pathway is the miss-ing link. This pathway is an evolutionarilyconserved signalling mechanism that regu-lates lineage choices in a variety of cell types,including T cells7. There are four mam-malian Notch receptors and five Notch ligands; the latter fall into two structurallydistinct classes, Jagged and Delta. When theNotch receptor binds one of its ligands, theintracellular domain of Notch is cleaved togenerate an active form of the receptor. Thismigrates into the nucleus, where it caninduce gene expression by activating thetranscription factor RBPJ�.

Amsen et al.1 show that under differentconditions dendritic cells can be induced toexpress either the Jagged or the Delta class ofNotch ligands. Delta is induced on dendriticcells exposed to a Th1-promoting stimulus,

lipopolysaccharide, which is a component ofbacterial cell walls. This acts through theconventional Toll-like receptor pathway. Incontrast, Jagged is induced under conditionsthat have previously been shown to induceTh2 responses.The authors present evidencethat Notch ligands are involved in polarizingthe T-cell response towards producing oneor the other type of effector cell. They showthat dendritic cells that have been engineeredto express either Delta or Jagged on their surface promote induction of Th1 or Th2responses, respectively. They also show thatthe promoter/enhancer region of the IL-4gene contains three binding sites for RBPJ�,and that Notch can activate gene transcrip-tion via these sites.

The notion that Notch signals promoteproduction of Th2 cells is supported by com-plementary findings from studies of CD4 T-cell responses in mice in which the T cellscannot produce RBPJ�. In separate analyses,Amsen et al.1 and Tanigaki et al.2 both findthat the balance between Th1 and Th2 differ-entiation is perturbed in these mice. RBPJ�-deficient T cells differentiate poorly intoIL-4-producing Th2 cells, and preferentiallydevelop into Th1 cells producing IFN-�.Thedifferent subsets of T cells regulate the type of antibody produced during an immuneresponse, and Tanigaki et al. report that anti-body responses are also skewed in mice lack-ing RBPJ� in their T cells. The mice havefewer of the antibodies that are normallyassociated with Th2 responses, and moreTh1-type antibodies. Together, these resultssuggest that Notch signals can alter the balance of CD4 T-cell differentiation into the Th1 or Th2 lineage.

These findings are exciting, but of coursequestions still remain. How, for instance, arethe different Notch ligands able to transducedistinct signals to naive T cells? If the Notchligands Delta and Jagged can induce CD4 T cells to adopt opposing fates, and Notchpromotes Th2 differentiation by activatinggene transcription via RBPJ�, then onlyJagged should activate this RBPJ�-depen-dent programme. But it is unclear how thisdistinction is made: in some settings at least,both classes of ligand are able to activateRBPJ�-dependent signals8. Divergent sig-nals could result from the specificity ofNotch ligands for different Notch familymembers.Or Notch ligands might transducedistinct signals through a single receptor, forexample through RBPJ�-dependent orRBPJ�-independent pathways. The impor-tance of retaining two classes of Notch lig-ands is underscored by the fact that simplerorganisms, which possess a single Notchreceptor, also have two classes of ligands thatdo not signal equivalently9. We eagerly awaitanalyses that will unravel the complexities ofNotch signalling in naive CD4 T cells. ■

Sophie M. Lehar and Michael J. Bevan are in theDepartment of Immunology and Howard Hughes

1. Glazebrook, K. et al. Nature 430, 181–184 (2004).

2. Cimatti, A. et al. Nature 430, 184–187 (2004).

3. Blumenthal, G. R. et al. Nature 311, 517–525 (1984).

4. Steidel, C. C., Adelberger, K. L., Giavalisco, M., Dickinson, M. &

Pettini, M. Astrophys. J. 519, 1–17 (1999).

5. Dickinson, M., Papovich, C., Ferguson, H. C. & Budávari, T.

Astrophys. J. 587, 25–40 (2003).

6. Fontana, A. et al. Astrophys. J. 594, L9–L12 (2003).

7. Drory, N. et al. Astrophys. J. 562, L111–L114 (2001).

8. Franx, M. et al. Astrophys. J. 587, L79–L82 (2003).

9. Somerville, R. S. in Proc. ESO/USM/MPE Workshop on

Multiwavelength Mapping of Galaxy Formation and Evolution

(eds Bender, R. & Renzini, A.). Preprint at

http://arxiv.org/abs/astro-ph/0401570 (2004).

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