{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T03:20:01Z","timestamp":1789874401059,"version":"4.0.1"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2013,12,1]],"date-time":"2013-12-01T00:00:00Z","timestamp":1385856000000},"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":[[2013,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Control of Leishmania infantum infection is dependent upon Th1 CD4+ T cells to promote macrophage intracellular clearance of parasites. Deficient CD4+ T cell effector responses during clinical visceral leishmaniasis (VL) are associated with elevated production of IL-10. In the primary domestic reservoir of VL, dogs, we define occurrence of both CD4+ and CD8+ T cell exhaustion as a significant stepwise loss of Ag-specific proliferation and IFN-\u03b3 production, corresponding to increasing VL symptoms. Exhaustion was associated with a 4-fold increase in the population of T cells with surface expression of programmed death 1 (PD-1) between control and symptomatic populations. Importantly, exhausted populations of CD8+ T cells and to a lesser extent CD4+ T cells were present prior to onset of clinical VL. VL-exhausted T cells did not undergo significant apoptosis ex vivo after Ag stimulation. Ab block of PD-1 ligand, B7.H1, promoted return of CD4+ and CD8+ T cell function and dramatically increased reactive oxygen species production in cocultured monocyte-derived phagocytes. As a result, these phagocytes had decreased parasite load. To our knowledge, we demonstrate for the first time that pan-T cell, PD-1\u2013mediated, exhaustion during VL influenced macrophage-reactive oxygen intermediate production. Blockade of the PD-1 pathway improved the ability of phagocytes isolated from dogs presenting with clinical VL to clear intracellular parasites. T cell exhaustion during symptomatic canine leishmaniasis has implications for the response to vaccination and therapeutic strategies for control of Leishmania infantum in this important reservoir species.<\/jats:p>","DOI":"10.4049\/jimmunol.1301810","type":"journal-article","created":{"date-parts":[[2013,10,23]],"date-time":"2013-10-23T21:53:43Z","timestamp":1382565223000},"page":"5542-5550","source":"Crossref","is-referenced-by-count":159,"title":["Programmed Death 1\u2013Mediated T Cell Exhaustion during Visceral Leishmaniasis Impairs Phagocyte Function"],"prefix":"10.1093","volume":"191","author":[{"given":"Kevin J","family":"Esch","sequence":"first","affiliation":[{"name":"Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University , Ames, IA 50011"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Juelsgaard","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University , Ames, IA 50011"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro A","family":"Martinez","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University , Ames, IA 50011"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas E","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University , Ames, IA 50011"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine A","family":"Petersen","sequence":"additional","affiliation":[{"name":"Department of Veterinary Pathology, College of Veterinary Medicine, Iowa State University , Ames, IA 50011"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,12,1]]},"reference":[{"key":"2025032406005560800_r1","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1038\/nrmicro2608","article-title":"Leishmaniasis: complexity at the host-pathogen interface","volume":"9","author":"Kaye","year":"2011","journal-title":"Nat. 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