title: Splenic CD4+ T Cells in Progressive Visceral Leishmaniasis Show a Mixed Effector-Regulatory Phenotype and Impair Macrophage Effector Function through Inhibitory Receptor Expression.
abstract: Visceral leishmaniasis (VL), caused by infection with the intracellular protozoan Leishmania donovani, is a chronic progressive disease with a relentlessly increasing parasite burden in the spleen, liver and bone marrow. The disease is characterized by fever, splenomegaly, cachexia, and pancytopenia, and progresses to death if not treated. Control of Leishmania infection is mediated by Th1 (IFNγ-producing) CD4+ T cells, which activate macrophages to produce nitric oxide and kill intracellular parasites. However, despite expansion of CD4+ T cells and increased IFNγ expression in the spleen, humans with active VL do not control the infection. We used an experimental model of chronic progressive VL in hamsters, which mimics clinical and pathological features seen in humans, to better understand the mechanisms that lead to progressive disease. Transcriptional profiling of the spleen during chronic infection revealed expression of markers of both T cell activation and inhibition. CD4+ T cells isolated from the spleen during chronic progressive VL showed mixed expression of Th1 and Th2 cytokines and chemokines, and were marginally effective in controlling infection in an ex vivo T cell-macrophage co-culture system. Splenic CD4+ T cells and macrophages from hamsters with VL showed increased expression of inhibitory receptors and their ligands, respectively. Blockade of the inhibitory receptor PD-L2 led to a significant decrease in parasite burden, revealing a pathogenic role for the PD-1 pathway in chronic VL. PD-L2 blockade was associated with a dramatic reduction in expression of host arginase 1, but no change in IFNγ and inducible nitric oxide synthase. Thus, the expression of counter-regulatory molecules on splenic CD4+ T cells and macrophages promotes a more permissive macrophage phenotype and attenuates intracellular parasite control in chronic progressive VL. Host-directed adjunctive therapy targeting the PD-1 regulatory pathway may be efficacious for VL.
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Audrie A
authors.identifier: http://orcid.org/0000-0002-4917-666X
authors.initials: AA
authors.lastname: Medina-Colorado
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Elvia Y
authors.initials: EY
authors.lastname: Osorio
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Omar A
authors.initials: OA
authors.lastname: Saldarriaga
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.|Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America.|Center for Tropical Diseases, University of Texas Medical Branch, Galveston, Texas, United States of America.|Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Bruno L
authors.initials: BL
authors.lastname: Travi
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Fanping
authors.initials: F
authors.lastname: Kong
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, United States of America.|Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Heidi
authors.initials: H
authors.lastname: Spratt
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.|Center for Tropical Diseases, University of Texas Medical Branch, Galveston, Texas, United States of America.|Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, United States of America.|Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Lynn
authors.initials: L
authors.lastname: Soong
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.|Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, United States of America.|Center for Tropical Diseases, University of Texas Medical Branch, Galveston, Texas, United States of America.|Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, United States of America.|Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Peter C
authors.identifier: http://orcid.org/0000-0001-7320-7406
authors.initials: PC
authors.lastname: Melby
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018920:Coculture Techniques; D006224:Cricetinae; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007893:Leishmania donovani / Q000276:immunology; D007898:Leishmaniasis, Visceral / Q000235:genetics / Q000276:immunology* / Q000469:parasitology; D008213:Lymphocyte Activation / Q000235:genetics; D008262:Macrophage Activation / Q000235:genetics; D008264:Macrophages / Q000276:immunology*; D008297:Male; D008647:Mesocricetus; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000276:immunology
chemical_list: D016207:Cytokines; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger