The Journal of Experimental Medicine
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Published 19 July 2004. doi:10.1084/jem.20040298
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 2, 201-210
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Role for CD4+ CD25+ Regulatory T Cells in Reactivation of Persistent Leishmaniasis and Control of Concomitant Immunity

Susana Mendez1, Stacie K. Reckling2, Ciriacco A. Piccirillo1, David Sacks1, and Yasmine Belkaid2

1 Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
2 Division of Molecular Immunology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229

Address correspondence to Yasmine Belkaid, Division of Molecular Immunology, Cincinnati Children's Hospital Research Foundation, 3333 Burnet Ave., TCHRF 1565, Cincinnati, OH 45229. Phone: (513) 636-1340; Fax: (513) 636-5355; email: yasmine.belkaid{at}cchmc.org

Reactivation of dormant infections causes an immense burden of morbidity and mortality in the world at large. Reactivation can occur as a result of immunosuppression, environmental insult, or aging; however, the cause of reactivation of such infections is often not clear. We have previously shown that persistence of the parasite Leishmania major is controlled by endogenous CD4+ CD25+ regulatory T (T reg) cells. In this report, we show that despite efficient parasite clearance at secondary sites of infection, Leishmania superinfection can cause disease reactivation at the primary site. Our results strongly suggest that T reg cells, whose numbers increase in sites of reactivation, are directly responsible for such reactivation. Depletion of CD25+ cells at the time of secondary challenge prevented disease reactivation at the site of persistent infection while strengthening the expression of immunity at the site of secondary challenge. Finally, transfer of T reg cells purified from infected mice into chronically infected mice was sufficient to trigger disease reactivation and prevent the expression of an effector memory response. Our results demonstrate that after persistence is achieved, an equilibrium between T reg cells and effector lymphocytes, which can be disturbed by superinfection, controls the efficiency of recall immune responses and disease reactivation.

Key Words: Leishmania • reactivation • CD4+ CD25+ regulatory • T cells • memory • chronicity

S. Mendez's present address is Dept. of Microbiology and Tropical Medicine, George Washington University, Washington, DC 20037.

C.A. Piccirillo's present address is Dept. of Microbiology and Immunology, Host Resistance Laboratory, McGill University, Montreal QC H3A2B4, Canada.

Abbreviations used in this paper: BMDC, bone marrow–derived dendritic cells; T reg, regulatory T.


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