© 2002 Nature Publishing Group

HIGHLIGHTS

NATURE REVIEWS | IMMUNOLOGY VOLUME 3 | JANUARY 2003 | 3

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.

Many microbial infections, such as tuberculosis and malaria, arenever eliminated completely by ourimmune system, even though we canbe immune to a second attack. Now,a study in Nature shows that regula-tory T (T

Reg) cells at the site of

chronic infection might be crucialfor parasite persistence and long-lasting immunity.

Infection of C57BL/6 mice withLeishmania major results in a skinlesion that heals after 8–10 weeks,leaving the mouse with long-lastingimmunity to the parasite. But, a smallnumber of viable parasites persist.Belkaid and colleagues found that alarge number of CD4+ T cells are pre-sent at the chronically infected site, ofwhich 40–50% are CD25+.

The lesion-derived CD4+CD25+

T cells did not respond to mitogenicstimuli in vitro and, similar to thenaturally occurring CD4+CD25+ T

Reg

cells that have been described inautoimmune settings, they couldsuppress proliferation and the secre-tion of effector cytokines (such asinterferon-γ, IFN-γ) by CD4+CD25−

effector T cells.When stimulated with L. major-

infected dendritic cells (DCs) in vitro,CD4+CD25+ T cells from the chroniclesion produced large amounts ofinterleukin-10 (IL-10), but little IFN-γor T helper 2 (T

H2) cytokines, such

as IL-4 or IL-5. This seems to be anantigen-specific response, as DCsthat were infected with other para-sites or activated with CD40 failed toinduce the secretion of IL-10.

To test the function of these puta-tive T

Regcells in vivo, lesion-derived

T-cell subsets were transferred intolymphopaenic (Rag−/−) mice, whichwere then infected with L. major. Micethat received CD4+CD25− T cells werehighly resistant to infection, whereasthose that received CD4+CD25+

T cells developed severe disease. Micethat received a 1 to 10 ratio of CD25+

to CD25− T cells developed a healinglesion with persistent parasites, similarto the response of wild-type mice.This shows clearly that CD4+CD25+

lesion-derived T cells can suppress L. major immunity. Additionaladoptive-transfer experiments indi-cated that these regulatory cells origi-nate from the naturally occurringCD4+CD25+ regulatory T-cell pool.

This study shows that a fine bal-ance between regulatory and effectorT cells might be essential for parasite

persistence. But, it seems that thisphenomenon is not just of benefit tothe parasite. IL-10-deficient mice clearinfection completely, but, unlike wild-type mice, they do not have long-livedimmunity. So, by allowing the persis-tence of parasites, IL-10-secreting T

Reg

cells might benefit the host by main-taining protective immunity.

Jennifer Bell

References and linksORIGINAL RESEARCH PAPER Belkaid, Y. et al.CD4+CD25+ regulatory T cells control Leishmaniamajor persistence and immunity. Nature 420,502–507 (2002)FURTHER READING Shevach, E. M.CD4+CD25+ suppressor T cells: more questionsthan answers. Nature Rev. Immunol. 2, 389–400(2002) | Sacks, D. & Noben-Trauth, N. Theimmunology of susceptibility and resistance toLeishmania major in mice. Nature Rev. Immunol.2, 845–858 (2002)WEB SITESEthan Shevach’s lab:http://www.niaid.nih.gov/dir/labs/li/shevach.htmDavid Sacks’ lab:http://www.niaid.nih.gov/dir/labs/lpd/sacks.htm

Balancing act

I M M U N E R E G U L AT I O N