The Journal of Experimental Medicine
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Published 7 June 2004. doi:10.1084/jem.20040172
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 11, 1559-1566
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*Leishmaniasis
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Low Dose Leishmania major Promotes a Transient T Helper Cell Type 2 Response That Is Down-regulated by Interferon {gamma}–producing CD8+ T Cells

Jude E. Uzonna, Karen L. Joyce, and Phillip Scott

Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104

Address correspondence to Phillip Scott, Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104. Phone: (215) 898-1602; Fax: (215) 573-7023; email: pscott{at}vet.upenn.edu

An unresolved issue in the field of T helper (Th) cell development relates to the findings that low doses of antigen promote Th2 cell development in vitro, whereas several classic in vivo studies suggest the opposite. Here we resolve this paradox by studying the early immune response in mice after infection with different doses of Leishmania major. We found that low parasite doses induced a Th2 response in C57BL/6 (B6) mice, whereas high doses induced a Th1 response. However, the Th2 response in low dose–infected mice was transient and the animals healed. The appearance of a Th1 response after low dose infection was dependent upon the concomitant activation of interferon {gamma}–producing CD8+ T cells. In the absence of CD8+ T cells, the Th2 response was maintained. However, either neutralization of interleukin (IL)-4 or administration of IL-12 promoted a Th1 response after low dose infection of CD8-deficient mice, indicating that the required role for CD8+ T cells was limited to modulation of CD4+ T cell responses. Thus, the discrepant results seen between in vivo and in vitro studies on the effects of antigen dose on Th cell differentiation may depend upon whether CD8+ T cells participate in the immune response.

Key Words: Leishmania major • infection • CD8+ T cell • Th1/Th2 immune response • cytokines

Abbreviations used in this paper: CFSE, carboxyfluorescein diacetate succinimidyl ester; dLN, draining lymph node; SLA, soluble leishmanial antigen.


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