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© 2009 Modolell et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Modolell M, Choi B-S, Ryan RO, Hancock M, Titus RG, et al. (2009) Local Suppression of T Cell Responses by Arginase-Induced L-Arginine Depletion in Nonhealing Leishmaniasis. PLoS Negl Trop Dis 3(7): e480. doi:10.1371/journal.pntd.0000480

Abstract

The balance between T helper (Th) 1 and Th2 cell responses is a major determinant of the outcome of experimental leishmaniasis, but polarized Th1 or Th2 responses are not sufficient to account for healing or nonhealing. Here we show that high arginase activity, a hallmark of nonhealing disease, is primarily expressed locally at the site of pathology. The high arginase activity causes local depletion of L-arginine, which impairs the capacity of T cells in the lesion to proliferate and to produce interferon-γ, while T cells in the local draining lymph nodes respond normally. Healing, induced by chemotherapy, resulted in control of arginase activity and reversal of local immunosuppression. Moreover, competitive inhibition of arginase as well as supplementation with L-arginine restored T cell effector functions and reduced pathology and parasite growth at the site of lesions. These results demonstrate that in nonhealing leishmaniasis, arginase-induced L-arginine depletion results in impaired T cell responses. Our results identify a novel mechanism in leishmaniasis that contributes to the failure to heal persistent lesions and suggest new approaches to therapy.

Details

Title
Local Suppression of T Cell Responses by Arginase-Induced L-Arginine Depletion in Nonhealing Leishmaniasis
Author
Modolell, Manuel; Choi, Beak-San; Ryan, Robert O; Hancock, Maggie; Titus, Richard G; Abebe, Tamrat; Hailu, Asrat; Müller, Ingrid; Rogers, Matthew E; Bangham, Charles RM; Munder, Markus; Kropf, Pascale
Pages
e480
Section
Research Article
Publication year
2009
Publication date
Jul 2009
Publisher
Public Library of Science
ISSN
19352727
e-ISSN
19352735
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
1288101712
Copyright
© 2009 Modolell et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Modolell M, Choi B-S, Ryan RO, Hancock M, Titus RG, et al. (2009) Local Suppression of T Cell Responses by Arginase-Induced L-Arginine Depletion in Nonhealing Leishmaniasis. PLoS Negl Trop Dis 3(7): e480. doi:10.1371/journal.pntd.0000480