HIGHLIGHTS

T- C E L L D E V E LO P M E N TThe ageing
process
The appearance of grey hairs is just
one sign that a person is getting
older. Changes within our immune
system also occur as we age. Thethymus — the site of T-cell development — shrinks or involutes fromadolescence onwards. Until now, themolecular signals involved in themaintenance of the thymus havebeen unclear. Work by Sano andcolleagues in Immunity now shows
an essential role for signal transducer and activator of transcription 3(Stat3) in these processes.
Interactions between thymic stromal cells and lymphoid cells are vitalfor the formation and maintenance ofthymic structure. Stat3, a transcriptional regulator involved in growthfactor signalling, might be importantin these processes. As Stat3–/– mice die

LY M P H O C Y T E D E V E LO P M E N T

Decisions, decisions
T cell or B cell — what’s a lymphoidprogenitor to do? The molecular basis of thisfundamental cell-fate decision is not known,
although there are indications that Notch
signalling might be involved. Reporting inImmunity, Koch and co-workers provide
further support for the role of Notch1 in theT- versus B-cell-fate decision, and show that
lunatic fringe, a Notch regulator, caninfluence this choice — but in an unexpected
and novel way.
Notch proteins are evolutionarily
conserved receptors that are known to
direct cell-fate decisions in a variety ofdevelopmental settings. In the absence ofNotch1, B-cell development is promoted at
the expense T-cell development, and B cells
are found in the thymus. Conversely, in thepresence of a constitutively active Notch1,B-cell development is blocked, and T cells
develop in the bone marrow. These studies
imply that Notch1 expression normally
blocks B-cell commitment. But Notch
proteins do not act alone. The fringe family
are Golgi-resident proteins that are thought

to modulate Notch signalling in a cellautonomous manner by modifying theNotch receptors.
One fringe protein, lunatic fringe, isexpressed at high levels in the thymic
medulla but not in the thymic cortex, in
which immature thymocytes are found.
The authors constructed transgenic miceexpressing lunatic fringe under the controlof the p56lck proximal-promoter, which havehigh levels of lunatic fringe in the thymic
cortex. These mice have a striking reductionin the number of CD4–CD8–CD25+
pro-T cells in the thymus, where there isinstead an expanded population ofimmature B cells.
How does lunatic fringe disrupt thebalance of T- and B-lineage cells? To address
this question, transgenic and wild-type bonemarrow cells were transferred together into
irradiated Rag2–/– mice, which lack
lymphocytes and their precursors.
Transgenic bone marrow gave rise to thymic
B cells, as expected, but, surprisingly, so did
the non-transgenic cells. This shows lunatic

8 | OCTOBER 2001 | VOLUME 1

mid-gestation, the authors used
Cre/loxP technology to investigate therole of Stat3 in the maintenance ofthymic architecture. They crossed
Stat3 floxed mice with transgenics
that expressed Cre recombinase under
the control of the keratin 5 (K5) promoter, so that Stat3 was exclusively
deleted in stratified epithelial cells.
This is the first time this technique has
been used to successfully delete a genefrom thymic epithelial cells (TECs)
without affecting the genomes of thethymocytes. At birth thymocyte
development was normal in thesemice, but from adolescence onwards
the numbers of thymocytes in theStat3–/– mice decreased significantly incomparison with wild-type littermates. This thymic hypoplasia worsened with age, as did the observedchanges in cortical TEC architecture.
Stat3 activates the expression ofanti-apoptotic proteins, so theauthors next asked whether the agedependent thymic hypoplasia resulted from increased apoptosis. They
found more apoptotic thymocytes infringe can also act cell-non-autonomously.
The authors also show that ectopic
expression of lunatic fringe inhibits Notch1
activation in lymphoid progenitors
In these bone marrow chimaeras it isimpossible to tell whether lunatic fringe
promotes B-cell development merely bypromoting their expansion, or by directly
influencing the T- or B-cell-fate decision. To
test this, lymphoid progenitors from normal
mice were injected directly into the thymi oftransgenic or non-transgenic mice, and theirdevelopment was followed. In transgenic
thymi, up to 90% of the non-transgenic
lymphoid progenitors developed into Blineage cells and became mature B cells
through the normal developmentalprogramme.
The authors suggest that the choice ofT- versus B-cell fate can be influenced by
the degree of Notch1 activity inneighbouring progenitors, and ectopic
lunatic fringe biases towards the B-cell fatein the thymus. Whether lunatic fringe has aphysiological role in lineage commitment
remains to be seen.
Jen BellReferences and links
ORIGINAL RESEARCH PAPER Koch, U. et al. Subversionof the T/B lineage decision in the thymus by lunatic fringemediated inhibition of Notch-1. Immunity 15, 225–236(2001)

www.nature.com/reviews/immunol© 2001 Macmillan Magazines Ltd

the thymi of Stat3 –/– mice than inwild-type mice, and destruction of
the thymic architecture was evident.
When thymcytes were removed fromthe Stat3 mutant mice and exposedin vitro to apoptotic stimuli, the cells
were no more sensitive to apoptosis
than thymocytes from wild-typemice. So, the increased sensitivity ofthese cells is not due to an intrinsic
defect, but rather due to a failure of
the Stat3 –/– TECs to protect themfrom apoptotic stimuli.
In conclusion, these results showthat Stat3 is vital in the maintenanceof thymic architecture and for thesurvival of thymocytes. As far as thethymus goes then, Stat3 is a protein
you need if you want to maintaincontrol of the ageing process.
Jenny Buckland
References and links

I N N AT E I M M U N I T Y

ORIGINAL RESEARCH PAPER Sano, S et al.

Stat3 in thymic epithelial cells is essential for
postnatal maintenance of thymic architecture andthymocyte survival. Immunity 15, 261–273 (2001)
FURTHER READING

Anderson, G. & Jenkinson, E. J. Lymphostromalinteractions in thymic development and function.
Nature Rev. Immunol. 1, 31–40

New toll bridge
The Toll-like receptors (TLRs) are emerging as theprincipal antigen sensors of innate immunity. In theearliest stages of infection, members of the TLR family discern the nature of the invader by detecting its
conserved molecular patterns, and guide the ensuing
adaptive response by inducing cytokines and costimulatory molecules. It is unclear how exactly thisis achieved as all TLR-signalling components discovered to date are common to all TLRs and, indeed,interleukin-1 receptors (IL-1R). Two groups have
now discovered a novel adapter molecule that specifically interacts with TLR4 and is a crucial bridge inthe MyD88-independent signalling pathway.
MyD88 is a signalling adaptor containing aToll/IL-1R (TIR) domain, a conserved motif that isessential for TLR signal transduction. Previous
studies on MyD88-deficient mice, showed that thisadapter is vital for signalling by TLRs, with the only
known exception of TLR4 — a lipopolysaccharide(LPS) receptor — which can signal through both
MyD88-dependent and MyD88-independent pathways. However, the adapter in this alternative,
MyD88-independent pathway was not identified.
The new adaptor, described in the current studies,
was identified in database searches for novel TIR
domain-containing proteins. It is named TIR
domain-containing adapter protein (TIRAP) by
Horng et al., reporting in Nature Immunology; andMyD88-adapter-like (Mal), by Fitzgerald et al.,reporting in Nature. Notably, unlike MyD88,
TIRAP/Mal does not contain an amino-terminal
death domain.
Both groups assessed TIRAP/Mal function intransfection studies, and showed that, similar toMyD88, overexpression of TIRAP/Mal leads toactivation of nuclear factor κB (NF-κB). IsTIRAP/Mal, then, the elusive adapter of MyD88independent TLR signalling? To test this, bothgroups generated dominant-negative TIRAP/Malmutants. The mutant TIRAP/Mal was shown toinhibit NF-κB activation by TLR4, but did notinterfere with NF-κB activation by TLR9 (the CpG
receptor) or by IL-1R. Immunoprecipitation studies
confirmed that TIRAP/Mal does indeed physicallyassociate with TLR4.
To further investigate the functions ofTIRAP/Mal, Horng and co-workers synthesized apeptide that corresponds with the predicted siteof interaction with TLR4. This TIRAP/Mal peptide,
attached to a delivery peptide that allows it to penetrate the cell membrane, inhibits LPS-induced, but
not CpG-induced, NF-κB activation in a macrophagecell line. Furthermore, the TIRAP/Mal peptide wasshown to inhibit LPS-induced, but not CpG-induced,
upregulation of the co-stimulatory molecules
CD80/CD86, cytokine production, and developmentof antigen-presenting capacity in dendritic cells.
Uncovering this new adapter is an important stepin deciphering the complexity of TLR signalling, anddetermining which LPS-response genes are targets ofMyD88- or TIRAP/Mal-dependent pathways must
be a priority of future work.
Jen BellReferences and links
ORIGINAL RESEARCH PAPERS Horng, T., Barton, G.M. &Medzhitov, R. TIRAP: an adapter molecule in the Toll signaling pathway.
Nature Immunol. 2, 835–841 (2001) | Fitzgerald, K.A. et al. Mal(MyD88-adapter-like) is required for Toll-like receptor-4 signaltransduction. Nature 413, 78–83 (2001)
FURTHER READING Akira, S., Takeda, K. & Kaisho, T. Toll-likereceptors: critical proteins linking innate and acquired immunity. NatureImmunol. 2, 675–680 (2001)
WEB SITES

Luke O’Neill’s lab:
http://www.tcd.ie/Biochemistry/LONeill.html
Ruslan Medzhitov’s lab:
http://info.med.yale.edu/immuno/fac_medzhitov.html

NATURE REVIEWS | IMMUNOLOGYVOLUME 1 | OCTOBER 2001 | 9© 2001 Macmillan Magazines Ltd