RESEARCH

HIGHLIGHTS

HIGHLIGHT ADVISORS

CEZMI AKDIS

SWISS INSTITUTE OF ALLERGYAND ASTHMA RESEARCH,SWITZERLAND

BRUCE BEUTLER

SCRIPPS RESEARCH INSTITUTE,USA

PETER CRESSWELL

YALE UNIVERSITY, USA

JAMES DI SANTO

PASTEUR INSTITUTE, FRANCE

GARY KORETZKY

UNIVERSITY OFPENNSYLVANIA, USA

CHARLES MACKAY

GARVAN INSTITUTE OFMEDICAL RESEARCH,AUSTRALIA

CORNELIS J. M. MELIEF

LEIDEN UNIVERSITY MEDICALCENTRE, THE NETHERLANDS

MICHEL NUSSENZWEIG

THE ROCKEFELLER UNIVERSITY,USA

SARAH ROWLAND-JONES

CENTRE FOR TROPICALMEDICINE, OXFORD, UK

ALAN SHER

NATIONAL INSTITUTE OFALLERGY AND INFECTIOUSDISEASE, USA

ANDREAS STRASSER

THE WALTER AND ELIZA HALLINSTITUTE, AUSTRALIA

MEGAN SYKES

HARVARD MEDICAL SCHOOL,USA

ERIC VIVIER

CENTRE D’IMMUNOLOGIE DEMARSEILLE-LUMINY, FRANCE

MATTHIAS VON HERRATH

LA JOLLA INSTITUTE FORALLERGY AND IMMUNOLOGY,USA.

New research published in TheJournal of Immunology shows thatantigen-presenting cells such asdendritic cells (DCs) are not alwaysrequired to link innate immune sig-nals through Toll-like receptors(TLRs) to adaptive T-cell responses.This study showed that TLR expres-sion by T cells can lead to directeffects of pathogen-associated mole-cular patterns (PAMPs) on adaptiveimmunity.

Stimulation of TLRs on DCsresults in DC maturation andinduces the upregulation of MHCand co-stimulatory molecules andthe production of pro-inflammatorycytokines. The mature DCs in turnpresent antigen to, and stimulate,T cells. However, in this study, acti-vated mouse CD4+ T cells were alsoshown to express TLRs, indicatingthe possibility of a direct effect.Specifically, purified CD4+CD25–

T cells expressed mRNA encodingTLR3 and TLR9 but not TLR2 andTLR4. In the absence of suitablemonoclonal antibodies to detectTLR protein, the mRNA results wereconfirmed by stimulation with theTLR3 ligand poly(I:C) and the TLR9ligand CpG-containing DNA. Theseligands induced nuclear factor-κB(NF-κB) and mitogen-activated pro-tein kinase (MAPK) activation in theactivated T cells, in contrast to theTLR4 ligand lipopolysaccharide.

Having shown that T-cell TLR3and TLR9 are functional in terms ofsignalling, Laurence Turka and col-leagues looked at the downstream

effects. They showed that stimulationwith poly(I:C) or CpG-containingDNA increased the survival of a puri-fied population of activated CD4+

T cells in vitro. The increase in viablecell number occurred without anychange in proliferation. When acti-vated T cells were stimulated withpoly(I:C) or CpG DNA and thenadoptively transferred into congenichosts, survival was also increased in vivo compared with unstimulatedcells, as indicated by an increasedpercentage of transferred T cells inthe host spleen and an increased proliferative response to restimula-tion with the cognate antigen.Therefore, TLR signalling in T cellsmight improve memory responsesby promoting the survival of T cellsafter primary stimulation.

Using specific inhibitors, the T-cellsurvival response mediated by TLRswas shown to depend on NF-κB butnot MAPK activation. Consistent

with previous knowledge of TLR sig-nalling, CpG-DNA-mediated survivalthrough TLR9 depended on theadaptor molecule MyD88, whereaspoly(I:C)-mediated survival throughTLR3 did not. This indicates that bothMyD88-dependent and -independentpathways can activate NF-κB to medi-ate increased survival in T cells. Theend result of these two pathways wasupregulation of expression of theanti-apoptotic molecule BCL-X

L.

The authors speculate that theability of T cells to respond directlyto PAMPs, without using DCs as anintermediary, might be one way inwhich we have evolved to deal withpathogens that try to evade theimmune system by inhibiting DCfunction.

Kirsty Minton

References and linksORIGINAL RESEARCH PAPER Gelman, A. E.,Zhang, J., Choi, Y. & Turka, L. A. Toll-like receptorligands directly promote activated CD4+ T-cellsurvival. J. Immunol. 172, 6065–6073 (2004).

Cutting out the middle man

T- C E L L R E S P O N S E S

488 | JULY 2004 | VOLUME 4 www.nature.com/reviews/immunol

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