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* Department of Microbiology, Immunology and Tropical Medicine, George Washington University Medical Center, Washington, DC 20037; and
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
BALB/c IL-4R
–/– mice, despite the absence of IL-4/IL-13 signaling and potent Th2 responses, remain highly susceptible to Leishmania major substain LV39 due exclusively to residual levels of IL-10. To address the contribution of CD4+CD25+ T regulatory (Treg) cells to IL-10-mediated susceptibility, we depleted CD4+CD25+ cells in vivo and reconstituted IL-4R x RAG2 recipients with purified CD4+CD25– T cells. Although anti-CD25 mAb treatment significantly decreased parasite numbers in IL-4R–/– mice, treatment with anti-IL-10R mAb virtually eliminated L. major parasites in both footpad and dermal infection sites. In addition, IL-4R x RAG2 mice reconstituted with CD4+ cells depleted of CD25+ Treg cells remained highly susceptible to infection. Analysis of L. major-infected BALB/c and IL-4R–/– inflammatory sites revealed that the majority of IL-10 was secreted by the CD4+Foxp3– population, with a fraction of IL-10 coming from CD4+Foxp3+ Treg cells. All T cell IFN-
production was also derived from the CD4+Foxp3– population. Nevertheless, the IL-4R–/–-infected ear dermis, but not draining lymph nodes, consistently displayed 1.5- to 2-fold greater percentages of CD4+CD25+ and CD4+Foxp3+ Treg cells compared with the BALB/c-infected dermis. Thus, CD4+Foxp3– T cells are a major source of IL-10 that disrupts IFN- activity in L. major-susceptible BALB/c mice. However, the increase in CD4+Foxp3+ T cells within the IL-4R–/– dermis implies a possible IL-10-independent role for Treg cells within the infection site, and may indicate a novel immune escape mechanism used by L. major parasites in the absence of IL-4/IL-13 signaling.
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1 This work was supported by National Institutes of Health Grant AI054717 (to N.N.-T.).
2 Current address: Infectionology and Immunology on Organ Transplants, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan. E-mail address: hnagase{at}sch.md.shinshu-u.ac.jp
3 Address correspondence and request reprints to Dr. Nancy Noben-Trauth, Department of Microbiology, Immunology and Tropical Medicine, George Washington University Medical Center, Ross Hall, Room 407, 2300 Eye Street NW, Washington, DC 20037. E-mail address: nnoben{at}gwu.edu
4 Abbreviations used in this paper: Treg, T regulatory; CT, cycle threshold; KO, knockout; LN, lymph node; pm, promastigote; qPCR, quantitative PCR; SLA, soluble Leishmania Ag.
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  E. Bourreau, C. Ronet, E. Darcissac, M. C. Lise, D. Sainte Marie, E. Clity, F. Tacchini-Cottier, P. Couppie, and P. Launois Intralesional Regulatory T-Cell Suppressive Function during Human Acute and Chronic Cutaneous Leishmaniasis Due to Leishmania guyanensis Infect. Immun., April 1, 2009; 77(4): 1465 - 1474. [Abstract] [Full Text] [PDF]
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