title: PD-1 Co-inhibitory and OX40 Co-stimulatory Crosstalk Regulates Helper T Cell Differentiation and Anti-Plasmodium Humoral Immunity.
abstract: The differentiation and protective capacity of Plasmodium-specific T cells are regulated by both positive and negative signals during malaria, but the molecular and cellular details remain poorly defined. Here we show that malaria patients and Plasmodium-infected rodents exhibit atypical expression of the co-stimulatory receptor OX40 on CD4 T cells and that therapeutic enhancement of OX40 signaling enhances helper CD4 T cell activity, humoral immunity, and parasite clearance in rodents. However, these beneficial effects of OX40 signaling are abrogated following coordinate blockade of PD-1 co-inhibitory pathways, which are also upregulated during malaria and associated with elevated parasitemia. Co-administration of biologics blocking PD-1 and promoting OX40 signaling induces excessive interferon-gamma that directly limits helper T cell-mediated support of humoral immunity and decreases parasite control. Our results show that targeting OX40 can enhance Plasmodium control and that crosstalk between co-inhibitory and co-stimulatory pathways in pathogen-specific CD4 T cells can impact pathogen clearance.
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Zander
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
authors.forename: Nyamekye
authors.initials: N
authors.lastname: Obeng-Adjei
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Jenna J
authors.initials: JJ
authors.lastname: Guthmiller
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Divine I
authors.initials: DI
authors.lastname: Kulu
authors.affiliation: Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Mali International Center of Excellence in Research, University of Sciences, Techniques and Technology of Bamako, Bamako BP E.1805, Mali.
authors.forename: Aissata
authors.initials: A
authors.lastname: Ongoiba
authors.affiliation: Mali International Center of Excellence in Research, University of Sciences, Techniques and Technology of Bamako, Bamako BP E.1805, Mali.
authors.forename: Boubacar
authors.initials: B
authors.lastname: Traore
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Crompton
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. Electronic address: noah-butler@ouhsc.edu.
authors.forename: Noah S
authors.initials: NS
authors.lastname: Butler
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D005786:Gene Expression Regulation; D006801:Humans; D056724:Immunity, Humoral; D008288:Malaria / Q000276:immunology*; D051379:Mice; D010961:Plasmodium / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D053262:Receptors, OX40 / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology*
chemical_list: C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D053262:Receptors, OX40; C505716:TNFRSF4 protein, human