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The p110 Isoform of Phosphatidylinositol 3-Kinase Controls Susceptibility to Leishmania major by Regulating Expansion and Tissue Homing of Regulatory T Cells¹

Dong Liu^*, Tingting Zhang^*, Aaron J. Marshall^*, Klaus Okkenhaug, Bart Vanhaesebroeck and Jude E. Uzonna^2,*

^* Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada; Laboratory of Lymphocyte Signalling and Development, Babraham Institute Cambridge, Cambridge, United Kingdom; and Centre for Cell Signalling, Institute of Cancer, Queen Mary University of London, London, United Kingdom

Resistance to Leishmania major and most intracellular pathogens is usually associated with a strong T cell-mediated immunity, particularly a CD4⁺ Th1 response. Mice with an inactivating knock-in mutation in the p110 isoform of PI3K (referred to as p110^D910A) show severely impaired T cell responses. Because a strong T cell response is thought to mediate resistance to intracellular pathogens, we examined the outcome of L. major infection in p110^D910A mice. Paradoxically, p110^D910A mice on "resistant" and "susceptible" genetic backgrounds showed more robust resistance manifested as significantly reduced lesion size and accelerated parasite clearance. This enhanced resistance was associated with dramatically diminished immune responses, including impaired cell proliferation and effector cytokine (IFN- and TNF) production. Interestingly, the ability of macrophages and dendritic cells from p110^D910A mice to produce NO and destroy Leishmania parasites was similar to those of wild-type mice. We show that the enhanced resistance of p110^D910A mice was due to impaired expansion and effector functions of regulatory T cells (Tregs). Adoptive transfer studies demonstrated that p110^D910A mice lost their increased resistance when given enriched Tregs from wild-type mice. We suggest on the basis of these and further observations that the lack of this enzyme prominently affects Treg expansion and homing to infection sites, and that in the absence of Tregs, weak Th1 responses are capable of containing parasites and prevent pathology. We also suggest that temporary pharmacological inhibition of this enzyme may be a very effective form of treatment against cutaneous leishmaniasis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Funding for this study was provided by the Canadian Institutes of Health Research, Canadian Foundation for Innovation, and the Manitoba Health Research Council. J. E. Uzonna is a recipient of the CIHR New Investigator Award.

² Address correspondence and reprint requests to Dr. Jude Uzonna, Parasite Vaccines Development Laboratory, Department of Immunology, University of Manitoba, Winnipeg, Manitoba R3E 0W3, Canada. E-mail address: uzonna{at}cc.umanitoba.ca

³ Abbreviations used in this paper: Treg, regulatory T cell; BMDC, bone marrow-derived dendritic cell; BMDM, bone marrow-derived macrophage; DC, dendritic cell; dLN, draining lymph node; SLA, soluble Leishmania Ag; WT, wild type.

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The JI 2009 183: 1501-1502. [Full Text]