Journal article
PD-1 Co-inhibitory and OX40 Co-stimulatory Crosstalk Regulates Helper T Cell Differentiation and Anti-Plasmodium Humoral Immunity
Cell host & microbe, Vol.17(5), pp.628-641
05/13/2015
DOI: 10.1016/j.chom.2015.03.007
PMCID: PMC4433434
PMID: 25891357
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.
Details
- Title: Subtitle
- PD-1 Co-inhibitory and OX40 Co-stimulatory Crosstalk Regulates Helper T Cell Differentiation and Anti-Plasmodium Humoral Immunity
- Creators
- Ryan A Zander - Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USANyamekye Obeng-Adjei - Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USAJenna J Guthmiller - Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USADivine I Kulu - Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USAJun Li - Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USAAissata Ongoiba - Mali International Center of Excellence in Research, University of Sciences, Techniques and Technology of Bamako, Bamako BP E.1805, MaliBoubacar Traore - Mali International Center of Excellence in Research, University of Sciences, Techniques and Technology of Bamako, Bamako BP E.1805, MaliPeter D Crompton - Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USANoah S Butler - Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. Electronic address: noah-butler@ouhsc.edu
- Resource Type
- Journal article
- Publication Details
- Cell host & microbe, Vol.17(5), pp.628-641
- Publisher
- United States
- DOI
- 10.1016/j.chom.2015.03.007
- PMID
- 25891357
- PMCID
- PMC4433434
- ISSN
- 1931-3128
- eISSN
- 1934-6069
- Grant note
- 1K22AI099070 / NIAID NIH HHS K22 AI099070 / NIAID NIH HHS T32AI007633 / NIAID NIH HHS T32 AI007633 / NIAID NIH HHS P20 GM103447 / NIGMS NIH HHS 8P20GM103447 / NIGMS NIH HHS
- Language
- English
- Date published
- 05/13/2015
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984001145602771
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