{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T12:46:58Z","timestamp":1791118018756,"version":"4.1.0"},"reference-count":60,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2009,8,1]],"date-time":"2009-08-01T00:00:00Z","timestamp":1249084800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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\u03b4 isoform of PI3K (referred to as p110\u03b4D910A) 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\u03b4D910A mice. Paradoxically, p110\u03b4D910A mice on \u201cresistant\u201d and \u201csusceptible\u201d 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-\u03b3 and TNF) production. Interestingly, the ability of macrophages and dendritic cells from p110\u03b4D910A mice to produce NO and destroy Leishmania parasites was similar to those of wild-type mice. We show that the enhanced resistance of p110\u03b4D910A mice was due to impaired expansion and effector functions of regulatory T cells (Tregs). Adoptive transfer studies demonstrated that p110\u03b4D910A 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.<\/jats:p>","DOI":"10.4049\/jimmunol.0901099","type":"journal-article","created":{"date-parts":[[2009,7,14]],"date-time":"2009-07-14T01:43:38Z","timestamp":1247535818000},"page":"1921-1933","source":"Crossref","is-referenced-by-count":77,"title":["The p110\u03b4 Isoform of Phosphatidylinositol 3-Kinase Controls Susceptibility to <i>Leishmania major<\/i> by Regulating Expansion and Tissue Homing of Regulatory T Cells"],"prefix":"10.1093","volume":"183","author":[{"given":"Dong","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Immunology, University of Manitoba , Winnipeg, Manitoba,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Manitoba , Winnipeg, Manitoba,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron J","family":"Marshall","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Manitoba , Winnipeg, Manitoba,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Okkenhaug","sequence":"additional","affiliation":[{"name":"Laboratory of Lymphocyte Signalling and Development, Babraham Institute Cambridge , Cambridge,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart","family":"Vanhaesebroeck","sequence":"additional","affiliation":[{"name":"Centre for Cell Signalling, Institute of Cancer, Queen Mary University of London , London,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jude E","family":"Uzonna","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Manitoba , Winnipeg, Manitoba,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,8,1]]},"reference":[{"key":"2025032619491586400_R1","first-page":"151","article-title":"The regulation of immunity to Leishmania major.","volume-title":"Annu. 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